INVITED REVIEW
Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase

Nicole Defer, Martin Best-Belpomme, and Jacques Hanoune

Institut National de la Santé et de la Recherche Médicale U-99 Hôpital Henri Mondor, F-94010 Créteil, France


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
TISSUE SPECIFICITY OF mRNA...
TRANSCRIPTIONAL REGULATION OF...
POTENTIAL REGULATIONS OF...
FUNCTIONAL RELEVANCE OF...
GENERAL CONCLUSIONS
REFERENCES

The present review focuses on the potential physiological regulations involving different isoforms of adenylyl cyclase (AC), the enzymatic activity responsible for the synthesis of cAMP from ATP. Depending on the properties and the relative level of the isoforms expressed in a tissue or a cell type at a specific time, extracellular signals received by the G protein-coupled receptors can be differently integrated. We report here on various aspects of such regulations, emphasizing the role of Ca2+/calmodulin in activating AC1 and AC8 in the central nervous system, the potential inhibitory effect of Ca2+ on AC5 and AC6, and the changes in the expression pattern of the isoforms during development. A particular emphasis is given to the role of cAMP during drug dependence. Present experimental limitations are also underlined (pitfalls in the interpretation of cellular transfection, scarcity of the invalidation models, and so on).

adenylyl cyclase; calcium; calmodulin; kidney; heart; brain; spermatozoa; opiates; cannabis


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
TISSUE SPECIFICITY OF mRNA...
TRANSCRIPTIONAL REGULATION OF...
POTENTIAL REGULATIONS OF...
FUNCTIONAL RELEVANCE OF...
GENERAL CONCLUSIONS
REFERENCES

FORTY YEARS AFTER ITS DISCOVERY by Earl Sutherland, cAMP is still the archetypal "second messenger." But the cAMP signaling pathway, once considered to be simple and straightforward, has become very complex indeed. One reason is the fact that cAMP is acting not only by promoting protein phosphorylation via activation of protein kinase [protein kinase A (PKA)] but also by inducing protein-protein interaction independently of any phosphorylation (38, 81). Another reason is the extreme variety of potential regulations of cAMP synthesis and degradation, due to the multiplicity of phosphodiesterases (up to 40) and adenylyl cyclase (AC) isoforms.

The present review deals with the latter enzymes that convert ATP into cAMP. Today, at least nine closely related isoforms of AC, AC1-AC9, and two splice variants of AC8, have been cloned and characterized in mammals (63, 75, 145, 152). All of them share a large sequence homology in the primary structure of their catalytic site and the same predicted three-dimensional structure. Each of them consists of two hydrophobic domains (with 6 transmembrane spans) and of two cytoplasmic domains, resulting in a pseudosymmetrical protein. Only the cytoplasmic domains (C1 and C2), which constitute the catalytic site, are subject to intracellular regulations specific for each subtype. In particular the catalytic activity, as well as the sites for interaction with forskolin and Gsalpha , requires both cytoplasmic moieties. Elucidation of the structure-function relationship of ACs has markedly progressed over the last three years due to a series of recent studies, including crystallography and site-directed mutagenesis. The reader is referred to more detailed recent reviews dealing with those aspects (69, 158, 165).

The distinct properties of the individual isoforms allow them to play an interpretative role in signal transduction instead of being a linear pathway for the activity of the G protein-coupled receptors. Thus, depending on the properties and the relative level of the isoforms expressed in a tissue or a cell type, extracellular signals received by the G protein-coupled receptors can be differently integrated.

The present text will focus on the potential physiological regulations involving the different isoforms. Ideally, one should one day be able to correlate the existence of a specific AC isoform in a given tissue or cell with a specific function or "raison d'être." We are far from it at present and, if we want to avoid tedious phenomenological listings and descriptions, we can only grope for a few well-defined and physiologically relevant systems.

As is usual when commuting between analytic biochemical data and complex signaling networks, one is faced by many potential pitfalls. It is well known, for example, that 1) overexpressing a protein in a cell culture system can greatly alter the stoichiometry of the components of the network and lead to spurious results; 2) a well-defined regulation in vitro may be lost in vivo into a complex and redundant integrated system, (however, this specific regulation may show up in a pathological state); 3) some technical approaches may be too sensitive (e.g., the PCR reaction) or too unsatisfactory (we are still lacking good specific antibodies for all the AC isoforms) to provide unambiguous data; and 4) the probable marked differences in the specific activity of the various isoforms add a further degree of complexity when one analyzes the results of transfection experiments. This has been studied in the case of AC2 vs. AC6 (129), but most likely applies to most isoforms.

It is, therefore, with those caveats in mind that we present here a "progress report" on the cell- and isoform-specific regulations of cAMP synthesis.


    TISSUE SPECIFICITY OF mRNA EXPRESSION
TOP
ABSTRACT
INTRODUCTION
TISSUE SPECIFICITY OF mRNA...
TRANSCRIPTIONAL REGULATION OF...
POTENTIAL REGULATIONS OF...
FUNCTIONAL RELEVANCE OF...
GENERAL CONCLUSIONS
REFERENCES

Because of the unavailability of satisfactory antibodies for most of the isoforms, the tissue distribution has generally been determined by mRNA studies. Table 1 shows that, among the large diversity of the AC isoforms, some are widely expressed, such as AC2, AC4, and AC6, whereas others are more specifically expressed, for example AC1 in tissues of neural origin and AC5 in heart and striatum. Although mRNA for the various AC isoforms was found in brain, their expression is restricted to discrete structures of the central nervous system as demonstrated by in situ hybridization (cf. Table 1). This is particularly clear for the Ca2+/calmodulin-stimulated isoforms, AC1, AC3, and AC8. AC1 is abundant in the dentate gyrus of the hippocampus and the cerebral cortex (189), the highest expression of AC3 is exhibited in the olfactory neuroepithelium (188), whereas the important area for AC8 expression is the hypothalamus (16, 102), where it is the only Ca2+/calmodulin-stimulated isoform (110, 187, 188). In chick heart, AC5 is essentially expressed in myocytes, whereas AC6 is expressed in nonmyocyte cells (198). Moreover, the colocalization of the L-type Ca2+ channels with different elements of the cAMP-mediated signaling pathway, including AC in cardiomyocytes along the T tubule membranes (56), will provide new insights for understanding of the regulation of this pathway.

                              
View this table:
[in this window]
[in a new window]
 
Table 1.   Tissue-specific distribution of the adenylyl cyclase isoforms

The cellular heterogeneity of most of the tissues studied does not allow one to determine precisely in which type of cell from a given tissue a specific cyclase isoform is expressed, with the notable exception of kidney (18). At least five AC isoforms are expressed in rat kidney, AC6, AC5, AC4, AC7, and AC9, as found out by Northern blot (143, 179). The expression of AC4, AC5, and AC6 has been determined along the nephron. The pattern of distribution of AC6 suggests a greater concentration in the medulla than in the cortex. At the cellular level, this distribution is characterized by a widespread presence along the whole renal tubule. AC6 is more abundant in the distal segments (in the collecting tubule and in the thick ascending limb), whereas AC5 expression is restricted to the glomerulus and to the initial portions of the collecting duct, and AC4 only in the glomerulus (18). These observations raise the important questions as to whether more than one isoform can be expressed in one cell type and how it can be targeted within the cell compartments. Through the assay of hormone-dependent cAMP levels and on the basis of the properties of Ca2+-inhibitable AC isoforms, Chabardes et al. (18) proposed that "AC5 is mainly, if not exclusively, expressed in the glucagon-sensitive cells and that AC6 is present in the vasopressin-sensitive cells of the outer medullary collecting duct of the rat kidney." The functional relevance of AC localizations in the kidney will be described later.


    TRANSCRIPTIONAL REGULATION OF AC GENES
TOP
ABSTRACT
INTRODUCTION
TISSUE SPECIFICITY OF mRNA...
TRANSCRIPTIONAL REGULATION OF...
POTENTIAL REGULATIONS OF...
FUNCTIONAL RELEVANCE OF...
GENERAL CONCLUSIONS
REFERENCES

Whereas chromosomal localization of each of the nine isoforms has been determined both in human and in mouse (49, 60, 61, 66, 134, 150, 173) (Table 2), little is known concerning the promoter and the structure of the genes. Part of the promoter regions for AC3 and AC8 has been described with potential sequences for binding specific factors (115, 178). Moreover, 215,441 kb of the human chromosome 16p13.3 have been sequenced (GenBank accession no. AC005736), which should cover the complete AC9 gene. The AC9 gene extends over >150 kb and 9 introns.

                              
View this table:
[in this window]
[in a new window]
 
Table 2.   Chromosomal mapping of the adenylyl cyclases

AC3 was initially identified as the specific isoform of the olfactory neuroepithelium (10, 188). Several proteins of the olfactory signaling pathway, including the putative odorant receptor, Galpha olf, AC3, and the olfactory nucleotide-gated channel, have been identified and localized in the cilia by immunohistochemichal and electrophysiological methods (78, 107). Wang et al. (178) have identified binding sites for the olfactory neuron-specific transcription factor Olf-1 in the sequence surrounding the transcription initiation site of all these genes. This suggests that, in sensory neurons, the expression of these genes is coordinated and involves tissue-specific transcription factors. AC3 has also been found expressed in many other tissues, including bovine adipose tissue (20, 58), male germ cells (35, 57), and luteal cells from bovine ovaries (100). Expression of AC3 mRNA has also been detected in human islets isolated from nondiabetic individuals (193). Recently, two point mutations in the promoter region of the AC3 gene have been associated with a decrease in the glucose-induced insulin release in spontaneously diabetic rats, possibly through an alteration of AC mRNA transcription (1). It will be important to determine whether mutations in the AC3 gene promoter are also present in patients with type 2 diabetes.

The complete structure of the murine AC8 gene has been recently characterized (115). The AC8 gene extends over 18 exons, which encompass ~200 kb of the mouse genomic DNA. In the 5' end, a very long untranslated sequence (~2 kb upstream from the translation initiation site) is highly conserved among the different species, i.e., mouse, rat, and human (16, 36, 115). This suggests that posttranscriptional regulations play an important role in the expression and/or localization of AC8. As for the promoter region of the AC3 gene, the AC8 promoter does not contain any canonical TATA box but does include a consensus cAMP response element (CRE). The presence of a putative CRE sequence in the AC8 gene promoter might have some relevance because the induction of AC8 expression in specific regions of the brain during chronic administration of morphine (87, 103) is attenuated by injection of a cAMP-responsive element binding protein (CREB) antisense oligonucleotide (87), and because CREB (-/-)-mutant mice have reduced morphine abstinence syndrome (98).

All the sequence data available to date allow only limited conclusions. However, it is noteworthy that the structure of the different AC genes appears to be different: the first exon of AC3 is not translated (178), and <1 kb of the promoter region is sufficient to control the level of expression of this isoform (1). The mouse AC8 and human AC9 genes have a different exon organization with apparently no conservation of the splice donor sites, whereas some conservation exists between the mouse AC8 gene and the Drosophila melanogaster rutabaga gene (115). Finally, Muglia et al. (115) demonstrated that DNA sequences within the 10 kb preceding the first exon of the AC8 gene are critical for the establishment of region-specific pattern of expression of this isoform.


    POTENTIAL REGULATIONS OF MAMMALIAN ACs
TOP
ABSTRACT
INTRODUCTION
TISSUE SPECIFICITY OF mRNA...
TRANSCRIPTIONAL REGULATION OF...
POTENTIAL REGULATIONS OF...
FUNCTIONAL RELEVANCE OF...
GENERAL CONCLUSIONS
REFERENCES

As with most of the proteins involved in signal transduction, the fact that ACs exist as multiple isoforms with different regulatory properties (Table 3) allows complex signal integration, but may also lead to spurious conclusions. In most of the cases, regulatory properties of the cAMP-synthesizing machinery have been determined on purified membranes, and it is not clear by which combinatorial process the observed properties are integrated in the intact cells to produce a specific response to external stimuli. In some cases, the regulatory properties of individual isoforms have been determined in stably transfected, intact cells. Although these conditions permit the integration of informations from multiple signals, the transfection experiments are generally performed in cell types with low levels of cyclase activity or in cell types that do not express the transfected isoform. In those conditions, the physiological effectors needed for a given isoform may be absent, leading to nonreproducible data from cell type to cell type. Given the cell heterogeneity of most of the tissues, and the fact that most of the cells probably express multiple isoforms of AC, the analysis of the regulatory properties of one AC in its own context may be an unending challenge. The renal epithelial cells of the distal portion of the collecting tubule, where only one isoform, namely AC6, has been detected, may be an exception.

                              
View this table:
[in this window]
[in a new window]
 
Table 3.   Regulations of mammalian adenylyl cyclases

Stimulation by Gsalpha -Subunit and by Forskolin

Stimulation through Gsalpha is the major mechanism by which ACs are activated and the cAMP level is elevated. By expressing AC1, AC2, and AC6 in insect cells, Harry et al. (65) demonstrated that different ACs have different affinities for Gsalpha , which may provide an explanation for the various responses of different cell types to hormones and neurotransmitters that elevate cAMP. These differences are abolished in the presence of 100 µM forskolin. This indicates a conserved mechanism by which forskolin regulates Gsalpha coupling to the different ACs.

All ACs, with the possible exception of AC9, are activated by the diterpen forskolin. One major surprise in the elucidation of the structure of the ACs was the existence of a highly hydrophobic pocket at the interface of C1a/C2a, where forskolin acts. This pocket is different in AC9 compared with the other types of mammalian ACs. A single mutation transforming the Tyr1082 right-arrow Leu of mouse AC9 can confer both binding and activation by forskolin (192). At this position the Drosophila AC9 protein, which is forskolin-sensitive, contains a Leu (72). Together, forskolin and Gsalpha contribute for a higher cyclase activity. Gilman and colleagues (40, 157, 183) have shown that fragments of the two cytoplasmic domains of mammalian ACs can be synthesized independently as soluble proteins. On their mixture, both Gsalpha - and forskolin-stimulated activity can be restored. Using this system, Dessauer et al. (41) have characterized the interaction of AC with forskolin and ATP, although each one has its own binding site. The affinity of forskolin to AC is greatly reduced in the absence of Gsalpha (41).

Inhibition of AC Activity by Gi

The complexity of the hormonal control of AC was first evidenced by Rodbell and co-workers (138), who discovered the dual stimulatory and inhibitory G protein (Gi)-regulatory pathways. The inhibitory action of G protein-coupled receptors on AC activity can be blocked by pertussis toxin. Whereas all isoforms of ACs are potentially activated by Gsalpha -coupled receptors, the inhibition by Gialpha -coupled receptors appears to be isozyme specific; the alpha -subunit of the Gi protein, Gialpha , acts as a noncompetitive inhibitor of Gsalpha -stimulated AC5 and AC6 but has no effect on AC2 and AC8 (22, 85, 161, 163). Using a soluble enzyme system composed of the C1 and C2 domains of AC5 and AC2, the Gilman group (42) have demonstrated that only the C1 domain of AC5 retains the ability to bind Gialpha within a site close to the active site of the enzyme.

Regulations by the beta gamma -Subunits of the G Proteins

Classically, Gbeta gamma was thought to inhibit AC activity by chelating and deactivating stimulatory Gsalpha . The possibility of specifically expressing individual AC isoforms in cultured cells has led to a complete reappraisal of this view. 1) Gbeta gamma has no direct effect on the activity of a few isoforms (AC3, AC8, AC9) (134, 156). 2) Gbeta gamma activates AC2, AC4, and presumably AC7, directly, but only in the presence of activated Gsalpha (55, 95, 139, 156). This was a surprise and has the potential of explaining many aspects of cross-talk between different receptors (15, 53, 160, 199). For example, alpha 1-adrenergic stimulation of the Gqalpha -subunit can lead to an increase in cAMP through the beta gamma -complex, thus explaining the convergent action of Ca2+ and cAMP on the same target. Here again, the presence of specific isoforms of AC in a given cell will determine which regulatory pathways might be involved. Alternatively, a hormone or a neurotransmitter acting via a receptor normally coupled to Gi could produce a biphasic action on cAMP production depending on whether Gialpha or Gbeta gamma is predominantly influencing the enzyme (124, 125). 3) Finally, Gbeta gamma directly inhibits the calmodulin- or Gsalpha -stimulated AC1 activity (156, 162).

In contradiction to previous data (132, 196), Bayewitch et al. (11, 12) have also shown, by transient cotransfection into COS-7 cells of AC isoforms and beta - and gamma -heterotrimeric G subunit, that AC5 and AC6 are markedly inhibited by Gbeta gamma (particularly beta 1gamma 2), in conditions where AC2 activity is stimulated. If this were true in a physiological context, we would have then a new kind of cross-talk between receptors, whereby a receptor, not coupled to Gialpha or to AC, could inhibit the cAMP formation in an unexpected manner if AC1, AC5, or AC6 was the predominant isoform in a given tissue. However, whether this observation is physiologically relevant is not demonstrated at present.

Regulations by Protein Phosphorylation

Modulation of the enzymatic activity by phosphorylation is a common signature of downstream and feedback regulations in the transduction cascades. In this context, phosphorylation of the ACs by PKA provides a means of desensitization at the effector level. The profiles of the regulatory sensitivity of ACs to protein kinases is different according to each subtype. Both AC5 and AC6 are directly phosphorylated, and inhibited, by PKA (24, 74). Phosphorylation by PKA directly inhibits AC5 activity by decreasing the maximal velocity of the enzyme (74). Phosphorylation of AC6 at the level of Ser674 would disrupt the functional Gsalpha binding site, leading to the inhibition of AC activity (24). This mechanism could explain the cAMP-dependent desensitization of glucagon stimulation described several years ago in hepatocytes (133). This might be particularly important in the heart where AC5 and AC6 are the most abundant isoforms and where AC activity has to be strictly controlled. This suggests the presence of a negative feedback loop at the level of the cyclase itself as a potential mechanism of desensitization of the cAMP signaling pathway.

Phosphorylation by protein kinase C (PKC) often results from the activation of Gq and phospholipase C (PLC)-linked receptors, which in turn leads to mobilization of Ca2+, synthesis of diacylglycerol, and activation of PKC. On PKC activation, cAMP production within the cells is altered. Phorbol 12-myristate 13-acetate is able to increase AC activity in cells transfected with AC1, AC2, AC3, AC5, or AC7. Potentiation of AC1 activity by PKC can be observed only on Ca2+/calmodulin stimulation (76), whereas inhibition of AC4 activity by PKC-alpha is not observed on basal activity but after Gsalpha stimulation (201). Whether PKC directly modulates AC activity has been controversial. In insect cells, AC2 activity is clearly activated by PKC-alpha , but this activity is lost on membrane solubilization or AC2 purification, although it retains the stimulation by Gsalpha and forskolin (47). On the other hand, using purified PKC and AC, Kawabe et al. (80) have demonstrated that PKC-zeta can directly phosphorylate AC5, leading to a 20-fold increase in AC activity. Although PKC-alpha is less potent to activate AC5, the two PKCs are additive in their capacity to activate AC. Phosphorylation of AC5 by the different PKCs is particularly important in the heart, where growth factors including insulin are able to regulate cAMP production and contractility. In vitro, the alpha - and zeta -isoforms directly phosphorylate and activate AC5. Whereas the zeta -isozyme activates AC5 in a Ca2+-independent manner, the alpha -isozyme requires Ca2+. This affords another mechanism for the Ca2+-mediated regulation of AC5 activity in heart. In cells expressing AC5, insulin augments cAMP production through phosphatidylinositol-3,4,5 triphosphate (PIP3) activation of the PKC-zeta (79). In the heart, all hormones or growth factors that activate PI3-kinase, leading to the formation of PIP3, which activates PKC-zeta , would be able to control cAMP production through a direct activation of AC5. All these observations demonstrate that PKC can alter the ability of the AC isoforms to integrate signals derived from multiple inputs. ACs therefore appear to be important targets for direct or PKC-mediated modulatory effects of Ca2+. The other very important regulations of AC by Ca2+, either negative or positive, are dealt with later.

The mechanism by which a cell can integrate multiple signals to modulate AC activity is well documented in a paper of Marjamaki et al. (101). AC2, AC3, and AC4 have been transfected in DDT1-MF2 cells which already expressed AC6, AC7, AC8, and AC9. Whereas AC2 and AC4 exhibit a high amino acid sequence homology, and share most of their in vitro regulatory properties, they can be submitted to different hormonal regulations in vivo: in cells transfected with AC2 or AC4, alpha 2-adrenergic receptor (AR) stimulation initiates both positive (through beta gamma ) and negative (through Gi) effects on Gs-stimulated activity; however, PKC blocks the negative input from the alpha 2-AR in AC2-transfected cells, whereas it blocks the positive input in AC4-transfected cells (101). These observations demonstrate the complexity of integration of multiple signals by ACs. The authors concluded that this dynamic process is dependent on the enzyme type and the state of phosphorylation. The ability of the AC to integrate multiple information certainly plays a key role in the signaling plasticity observed during a wide range of physiological or pathological processes and during development.

Regulations by Ca2+

All AC activities are inhibited by high, nonphysiological concentrations of Ca2+ in the submillimolar range, possibly by competition with magnesium. In certain tissues, including the pituitary gland, platelets, and heart, AC activity has been reported to be inhibited by concentrations of Ca2+ in the micromolar range. This appears to be a feature of the two closely related cyclase isoforms, AC5 and AC6, cloned from heart, liver, kidney, striatum, Reuber hepatoma, or NCB-20 cells (30, 31, 111). When expressed in a variety of recipient cells lines, these isoforms are inhibited by micromolar concentrations of Ca2+, and the inhibition is additive to that elicited by receptors acting via Gialpha . Whether Ca2+ modulates AC5 and AC6 activities directly or via a Ca2+-binding protein remains to be determined.

Ca2+/calmodulin activates AC1 and AC8 by direct binding to a putative calmodulin binding site located in a C1b helical region of AC1 (90, 175) or in the C2 region of AC8 (59). The precise activation mechanism is unknown. It has been proposed, on the basis of other Ca2+/calmodulin binding proteins, that calmodulin binding would disrupt an autoinhibitory interaction between the C1b or C2b region and the catalytic core.

Conclusion

It thus appears that 1) the different ACs have different potential regulatory properties, delineated by their primary structure and/or activity in vitro; 2) the same effector can exert positive or negative effects on the various isoforms; 3) according to the specific pattern of protein expression in the different cell types, the same isoform may be regulated differently; and 4) finally, through Ca2+ regulations, the different signaling pathways, using the various G proteins, can talk together to (hopefully) better regulate cell functions. It is clear that the integration of the multiple signals by AC is a dynamic process and that the ability of the different AC types to respond to activated Gsalpha , Gialpha , Gbeta gamma , Ca2+, and phosphorylation places the enzyme at a central point for cross-talk between different signaling pathways.


    FUNCTIONAL RELEVANCE OF SPECIFIC ISOFORM EXPRESSION
TOP
ABSTRACT
INTRODUCTION
TISSUE SPECIFICITY OF mRNA...
TRANSCRIPTIONAL REGULATION OF...
POTENTIAL REGULATIONS OF...
FUNCTIONAL RELEVANCE OF...
GENERAL CONCLUSIONS
REFERENCES

Is the Inhibition of AC by Micromolar Concentration of Ca2+ Physiologically Relevant?

Heart and kidney are among the major organs in which Ca2+-inhibitable AC isoforms are predominant. However, it is difficult to clearly attribute a physiological role to this specific regulation. We and others have demonstrated that, although the two major isoforms in rat heart, AC5 and AC6, are equivalent at birth, the AC5 mRNA becomes predominant in the adult rat heart (52, 169). Sympathetic stimulation of cardiac tissue elevates cAMP, which in turn leads to an increase in intracellular Ca2+, and the wave of Ca2+ has been proposed to lead to a rhythmic dissipation of the cAMP signal (32). The capacitative entry of Ca2+, secondary to the emptying of intracellular Ca2+ pool (e.g., by the use of the Ca2+-ATPase inhibitor thapsigargin), has been proposed to play a major role in positively (AC1 or AC8) or negatively (AC5 or AC6) regulating AC activity (26, 33). That it is the only mechanism by which a change in cytosolic Ca2+ concentration can influence AC activity is probably still open to question, especially in excitable tissues where the capacitative entry of Ca2+ plays a minor role if any.

In fact, the relative effects of Ca2+ and cAMP are much more complex. We have just demonstrated that overexpression of AC8, a neural, Ca2+/calmodulin-stimulatable AC isoform in mice heart (91a) is not only compatible with normal heart function but even leads to enhanced function, with no cardiomegaly or fibrosis in 3-to 5-mo-old animals. If the rhythmic Ca2+ inhibition of cAMP formation were of major importance, we would have expected this transfection to be lethal.

In the kidney, the preferential distribution of AC6 in the medulla (143) is due to the presence of two segments, collecting tubule and thick ascending limb, in which AC6 is highly expressed (18). An important point is the subcellular location of the AC in the epithelial cells. It is generally accepted that AC is localized to the basolateral domain (144). However, a growing body of literature suggests that receptors are asymmetrically expressed in the renal epithelial cells: A1-adenosine receptors and beta 2-ARs are thought to mediate the effects of agonist exposure at the apical membrane (17, 64, 96), whereas the alpha 2B-AR is known to be expressed at the basolateral membrane of the proximal tubule cells (68). In this context, it has been proposed that apical beta 1-AR requires endocytosis to activate a basolateral AC in proximal tubule epithelial cells of rat kidney (64), which essentially express the AC6 isoform. On the other hand, Okusa et al. (123) have concluded that, in LLC-PK1 cells stably transfected with two G protein-coupled receptors known to be targeted to the opposite domains in the renal epithelial cells, the apical A1-adenosine receptor and the basolateral alpha 2B-AR, the AC activity is present at, or near, the apical and the basolateral domains of the cells and that the local AC activity can be regulated by Gi-coupled receptors. It therefore appears very important to determine the targeting of the various AC isoforms by using modern tools, such as flag labeling and confocal microscopy.

Depending on the cell type, the cytosolic free Ca2+ concentration ([Ca2+]i) can be increased by various mechanisms. Activation of PLC-coupled receptors, by substance K or bradykinin, causes an inhibition of the agonist-stimulated cAMP production: in C6-2B cells, which express mainly AC6, the inhibition of cAMP accumulation is temporally correlated with, and dependent on, initial [Ca2+]i rise evoked by Ca2+-mobilizing agents (34). In parathyroid cells, where extracellular free Ca2+ concentration ([Ca2+]e) plays a crucial role, eliciting a negative feedback on parathyroid hormone secretion, increasing [Ca2+]e stimulates PLC activity and inhibits hormone-dependent cAMP accumulation (21, 82). In kidney, the cortical thick ascending limb ensures the cAMP-stimulated paracellular Ca2+ reabsorption from the lumen to the extracellular fluid compartment of the renal tubule; an increase in [Ca2+]e decreases the hormone-dependent cAMP accumulation by a mechanism that is independent of direct inhibition of AC activity, most probably AC6 (18, 155). In both bovine parathyroid cells and in rat kidney, a Ca2+-sensing receptor has been described that is activated by [Ca2+]e and stimulates PLC activity. In the cortical thick ascending limb cells of rat kidney, this receptor is coexpressed with the Ca2+-inhibitable AC, AC6 (37). An increase in extracellular Ca2+, coupled to PLC activation, induces a dose-dependent inhibition of the vasopressin-dependent cAMP increase (155). Experiments on microperfused rat cortical thick ascending limb have demonstrated that [Ca2+]e inhibits the transtubular electrolyte reabsorption (37), which supports a direct physiological role for an inhibition of AC6. The best hypothesis to explain the inhibitory effect of extracellular Ca2+ on AC activity in the thick ascending limb (37) is an inhibition elicited by an increase in intracellular Ca2+ (due to capacitative Ca2+ entry and/or Ca2+ release).

Invalidation of the Gsalpha -subunit in mice has shed additional light on those mechanisms. In the thick ascending limb, acute exposure to vasopressin increases NaCl transport probably through the apical Na-K-2Cl cotransporter. In the heterozygous Gsalpha -knockout mice, the Na-K-2Cl cotransporter protein is markedly reduced (48). In parallel, cAMP production, on glucagon stimulation, and the abundance of AC6 are diminished in thick ascending limb. In this system the abundance of AC6 is probably regulated by a feed-forward regulatory mechanism (48), the amount of AC6 being positively correlated with that of Gsalpha and not subject to compensatory overexpression. Along the same line, it is interesting to note that all the AC isoforms expressed in the kidney were found to be depressed in the homozygous Brattleboro rats, animals with an hereditary diabetes insipidus (DI) lacking antidiuretic hormone (143), when one would have expected some compensatory increase.

AC5 and AC6 are inhibitable by both Gi-coupled receptors and Ca2+. The characteristics of inhibitory regulation of AC activity by Ca2+ and G proteins were examined in dispersed gastric smooth muscle cells. These inhibitions can be mediated independently by Gi proteins and Ca2+ influx. When both mechanisms are triggered concurrently, inhibition is exclusively mediated by Gi proteins (116).

The Role of Ca2+/Calmodulin-Activated ACs in Brain Function

The central nervous system possesses all the forms of ACs characterized so far. The presence of Ca2+-stimulated cyclase activity has been known for many years and is now ascribed to the two specific isoforms, AC1 and AC8.

AC1 has been the first isoform to be cloned (86). It can be activated by Gs-coupled receptors as well as by the Ca2+-calmodulin complex and, therefore, can function as a coincidence detector for the two signaling pathways. AC8 is also stimulated by Ca2+/calmodulin, albeit at a 5-10 times higher Ca2+ concentration. Although there is not definite evidence for it, AC8 is supposed to rather act as a pure Ca2+ detector (190).

AC1 is present in various areas of the brain, mainly the cortex, the hippocampus, the cerebellum, and the pineal gland. Interestingly, research in mammals has been driven by previous results obtained in Drosophila concerning mutations affecting memory. The flies can be trained to avoid a particular odor by coupling exposure to that odor with an electric shock. The rutabaga- mutant flies fail to avoid the "trained" odor and appear to be deficient in Ca2+-activated AC (43, 44, 94). This form of AC has been characterized and cloned by Levin et al. (89) and appears most similar to the mammalian AC1, with the exception of a very long COOH terminal, the function of one-half of which is unknown. A single point mutation at position 1026 is sufficient to cause the complete loss of cyclase activity in vitro and to result in the biochemical and phenotypical defects seen in vivo. All this points to a very important role of AC1 in learning and memory.

Disruption of the AC1 gene in mice results in a loss of Ca2+-sensitive AC activity in cerebellum, cortex, and hippocampus by 62, 38, and 46%, respectively (151, 172, 186), with no obvious anatomic differences. The mutant mice exhibit a dampening of the long-term potentiation in the hippocampus and a near-blockade in the cerebellum (171). A spontaneous loss-of-function mutation in the AC1 gene has also been reported in mice (barrelless) (2, 182). This mutation is associated with a partial failure of patterning of the whisker-to-barrel pathway, resulting in an incomplete formation of barreloids and an aberrant segregation of thalamocortical afferent arborization. It is therefore very likely that the AC1 signaling pathway plays an important role in pattern formation of the brain and in some forms of synaptic plasticity, including learning and memory storage. Whether this might be related to the pattern of appearance of AC1 during development as we reported (104) merits further investigation.

At the same time, AC1 does function as a good coincidence detector, and this is well demonstrated in the pineal gland (170), where AC1 is activated by norepinephrine via both the beta -AR (through Gsalpha ) and the alpha 1-AR (through Ca2+ release), to increase cAMP formation and ultimately N-acetyl transferase and melatonin synthesis. AC1 synthesis undergoes a striking circadian variation that makes it a key regulating step in melatonin production and release.

AC8 is also a major isoform in the brain although it has also been found in testis (36, 63) and lung (115). In the brain, it is mainly present throughout (16, 102, 115), especially in the cortex, cerebellum, brain stem, hypothalamus, hippocampus, and olfactory bulb. The specific localization in hypothalamic nuclei suggests a role in neuroendocrine function whereas its specific increase in some regions of the brain, and especially in the locus coeruleus during morphine administration and withdrawal, points to a role in drug dependence (87, 103).

It is interesting to note that another type of cyclase, AC9, is expressed to a high level in the brain (5). This isoform is weakly sensitive to forskolin and is not directly regulated by Ca2+ or beta gamma . It has been proposed to be inhibited by the Ca2+/calmodulin-activated protein phosphatase 2B (calcineurin), at least in mice (4, 6) but maybe not in humans (61). The kinase that potentially phosphorylates AC9 has not been identified. Interestingly, invalidation of this isoform in Caenorhabditis elegans prevents Gsalpha -induced neuronal cell death (13, 84). AC9 might therefore be an important regulator, especially related to signaling in motoneurons. It is tempting to speculate that AC9 may also play such a role in mammals although there is no evidence for it at present.

Is a Specific Isoform Associated With Cell Differentiation?

In many cell types, the intracellular concentration of cAMP affects the progression within the cell cycle. In some of them, growth-stimulatory effects have been observed, whereas in others inhibitory effects have been reported (46, 97). In most of the cases, it appears that elevation of intracellular cAMP, through Gsalpha or forskolin activation of AC, blocks the transfer of signal from the growth factor receptors to MAP kinases, through PKA-dependent phosphorylation (23, 62, 184). As with many other undifferentiated or dedifferentiated cell types in culture, NIH3T3 cells express AC6 at a high level, whose activity is inhibited by a variety of signals, including Ca2+, PKA, and PKC (75, 146). To investigate the potential role of a specific AC isoform in regulating proliferative responses, Smit et al. (147) have transfected NIH3T3 cells with different AC isoforms. They observed that overexpression of AC6 has no effect on the rate of cell proliferation; by contrast, overexpression of AC2, an isoform that is stimulated by PKC, resulted in inhibition of cell cycle progression and increased doubling time, resulting from an inhibition of signal flow from Ras to mitogen-activated protein kinase. Moreover, the suppressive effect of the platelet-derived growth factor-induced DNA synthesis was completely reversed by coexpression of a dominant negative mutant of PKA. Thus expression of specific isoforms of AC might function as an homeostatic element of proliferation.

The importance of cAMP in cell differentiation has been reported in various organisms and cell types. However, the molecular mechanism involved is still poorly known. To investigate the role of specific isoforms of AC during cell differentiation, we have used the P19 embryonic carcinoma cells, which are pluripotent stem cells that can mimic in vitro the first stages of cellular differentiation occurring during mouse embryogenesis (106). Retinoic acid treatment of P19 cells leads to neuronal differentiation, whereas DMSO induces differentiation into mesodermal derivatives including cardiomyocytes. We have shown that neuronal differentiation of P19 cells, which is mediated by the cAMP/PKA cascade in vivo as well as in vitro (126, 176), exhibits a stage-specific upregulation of specific mRNA isoforms of AC, AC2, AC5, and AC8 (92). On the other hand, mesodermal differentiation of P19 cells is accompanied by an increase in mRNAs for AC2, AC5, and AC6 (93). In both cases, cell contacts and inhibition of cell proliferation are required before differentiation. In both cases, the total AC activity was increased at least by 10-fold. This increase is mainly related to an increase in AC2 level, because the specific activity of AC2 is much higher than that of the other ACs (129). Together with results obtained in transfected cells, these results favor the hypothesis that AC2 expression at a high level is a prerequisite for arrest of cell proliferation, then allowing cell differentiation. It is noteworthy that AC2 and AC7, both of which are stimulated by PKC, are expressed largely in postmitotic neural cells and platelets, whereas cells that retained proliferative capability do not express significant levels of isoforms that can be activated by growth factors.

Isoform-Specific Regulations During Development

The two best-studied systems to date are the heart and the brain. We (52) and others (169) have demonstrated that, although the two major isoforms in rat heart, AC5 and AC6 mRNAs, are equivalent at birth, AC5 mRNA becomes predominant in the adult rat heart. Because the two forms are clearly related and are similarly regulated by Ca2+, there is no obvious physiological correlation for this genetic switch. One could hypothesize that the shift from AC6 to AC5 could be related to the state of cellular differentiation. Interestingly, AC5 is absent in skeletal muscle, where the major isoform is AC9 (Table 1).

After denervation, the levels of AC9 and AC2 mRNAs decrease in skeletal muscle whereas those of AC6 and AC7 are increased, the latter pattern being identical to that observed in the fetus and the neonate. These results indicate that changes in AC activities as well as AC mRNAs play an important role in muscle development as well as during muscle atrophy (154).

In rat brain, we have studied the developmental pattern of AC1, AC2, and AC5 during the postnatal period by in situ hybridization (104). One of the very interesting features found is that during the early postnatal stage, AC1 transcripts are very high in the central cortex, the striatum, and several regions involved in the sensory relay nuclei (such as the superior and inferior colliculus). These AC transcripts subsequently decrease rapidly in these regions, to be replaced, for example, by the AC5 transcript in the striatum, whereas they dramatically increase in the cerebellum and the hippocampus. These results demonstrate that the various ACs are expressed in the developing rat brain in a region- and age-specific manner and that they may thus be important not only for synaptic transmission (e.g.. for long-term potentiation and memory) but also in the differentiation and maturation of synapses between neuronal cells, especially in sensory pathways.

Is a Specific Isoform Associated With the Development and Function of Mature Spermatozoa?

The cAMP-dependent pathway is known to play a critical role in the expression of genes involved in haploid germ cell differentiation, and several reports have indicated the existence of a unique soluble form of AC in mammalian germ cells with properties that differ from those of somatic cells: this AC activity is insensitive to G proteins, fluoride, and forskolin and is associated with a low-molecular-weight fraction, ranging from 42 to 69 kDa (3, 83, 121, 148, 149). The low-molecular-weight isoform has been described in the cytosol of the early stages of spermatide cells, whereas the AC activity is membrane-bound in mature spermatozoa (3). That specialized isoforms are required for germ cell differentiation is suggested by observations in lower organisms, where an AC with unique structure and properties is expressed during the germinative stage (130).

A soluble AC isoform with a molecular mass of 48 kDa has recently been isolated from rat testis, and its cDNA has been sequenced (14). In transfected cells, this isoform seems to possess the catalytic properties of the soluble AC described in spermatid cells: it is Mn2+-dependent and insensitive to G protein or forskolin regulation. This isoform, preferentially expressed in testis, is unique because its presumptive catalytic domains are closely related to cyano- and myxobacteria ACs. However, it originates from a larger protein of 187 kDa, most probably by a proteolytic cleavage. Nevertheless, the distribution within the different types of cells present in testis, somatic, and germinal cells has not been reported, and it is difficult to attribute a definite function to this small form.

More interestingly, AC3, which has been identified as being specific to the olfactory apparatus, was found specifically expressed in rat male germ cells, from pachytene spermatocytes to spermatids, in the same subpopulation as other elements of the olfactory transduction pathway, putative odorant receptors, Galpha olf, and the transcription factor Olf-1 (35, 57). A more detailed study has indicated that AC3 is localized in the acrosome membrane of spermatids (57), suggesting a role of this AC in the biogenesis of acrosome and possibly in gamete production and fertilization. In olfactory epithelium, both AC3 and the olfactory Galpha - subunit Galpha olf have been localized to the same receptor cell compartment, the distal segments of the olfactory cilia (78, 107). Moreover, a selective localization of Galpha olf, putative odorant receptors, and associated desensitizing proteins have been shown in elongated spermatids and the midpiece of the sperm tail (142, and N. Defer, unpublished observations). Taken together, these observations are consistent with the hypothesis that the signal transduction system used in olfaction may also be used in the function of the mature spermatozoa and may be implicated in sperm chemotaxis during fertilization.

Is a Specific Isoform Associated with a Specific Hormone Action?

Studies from the laboratory of Patel and colleages (118) have shown that epidermal growth factor (EGF) produces inotropic and chronotropic action in rat heart by increasing cAMP accumulation. This EGF-elicitated stimulation of cellular cAMP accumulation in the heart is the result of stimulation of AC activity by a mechanism involving the participation of a Gs protein (119) and the tyrosine kinase activity of the EGF receptor (117). The EGF-receptor tyrosine kinase can phosphorylate Gsalpha on tyrosine residues, and this phosphorylation increases its ability to stimulate AC activity. HEK-293 cells have been transfected with different isoforms of ACs, AC1, AC2, AC5, and AC6 (25). EGF increased AC activity and cAMP accumulation only in cells expressing AC5. Because all isoforms are potentially stimulated by Gsalpha , these results suggest AC5 that activation reflects either the specific interaction between AC5 and the tyrosine-phosphorylated form of Gs or the presence of an additional regulatory element, potentially PKC-zeta , which could modify the sensitivity of the enzyme. In heart, growth factor-stimulated production of PIP3 through PI3K is able to stimulate PKC-zeta and activate AC5 by a mechanism independent of Ca2+ (91, 120).

Along the same line, another model is provided by the ATP stimulation of AC through purinergic receptors. For long time, it has been reported that extracellular purines act as intercellular messengers and exert a widespread influence on cellular function by acting through different types of cell surface receptors. Activation of P2Y purinoceptors has been linked to changes in the cAMP level. According to the cell type, purinoceptor activation may result in an increase in basal and stimulated cAMP production as observed in microvascular endothelial cells from adrenal medulla and in heart. ATP, which is released from the terminal sympathetic nerve together with norepinephrine under physiological conditions, increases the contractility of isolated cardiac preparations (88) and induces chronotropic and dromotropic effect on mammalian sinoatrial node, by binding to P2 purinoceptors. In ischemic hearts, ATP could also be a source of arrhythmia. In an attempt to demonstrate the mechanism by which purinergic stimulation of cardiomyocytes increases intracellular cAMP, Pucéat et al. (135) demonstrated that purinergic stimulation of cardiomyocytes increased intracellular cAMP content through a Gs-mediated activation of an AC (135). Using HEK-293-transfected cells, they demonstrated that AC5, but not AC4 or AC6, is responsive to the purinergic stimulation. Moreover, purinergic activation of AC is additive to that of isoproterenol in cardiomyocytes. It was thus suggested that purines might act as modulators of cell functions already regulated by other neuromediators released from the same nerve terminals.

During the course of pregnancy and at the onset of parturition, the contractile activity of the uterus is under the control of steroid hormones. Progesterone, which culminates at midpregnancy, enhances myometrium relaxation by increasing the Gs-coupled beta 2-AR cAMP cascade (29, 50, 99, 174). The regulation of myometrium contractility implicates the AC-stimulatory pathways as a key component modulating the intracellular cAMP concentration and thus the contractile state of the uterus. Northern blot analysis revealed the presence of numerous isoforms in both humans and rats, AC6 being the major ones (109, 153). The level of expression of the AC mRNAs increases 1.7- to 3.4-fold during the course of pregnancy and diminishes near term and after delivery. In agreement with these findings, both basal and forskolin-stimulated AC activities exhibited a two- to threefold increase during the course of pregnancy, followed by a slight decrease near term (153). These data indicate that changes in the level of AC mRNA (and presumably proteins) that occur during pregnancy and after delivery may contribute to the essential role of cAMP in maintaining uterus quiescence. In this respect, the papers by Mhaouty et al. (108, 109) are particularly relevant. They have identified two types of Gi-coupled alpha 2-AR in rat myometrium: alpha 2A-AR transcript is present at midpregnancy, whereas alpha 2B-AR mRNA is detected at term (108). At midpregnancy, the activation of the alpha 2A-AR/Gi signaling cascade by micromolar concentration of clonidine, results in a potentiation of the beta 2-AR stimulation of the AC activity in myometrial membranes (108); addition of alpha -transducin, a Gbeta gamma scavenger, blocks this potentiation in a dose-dependent manner (109). At the time of delivery, [Ca2+]i dramatically increases in response to external stimuli and may inhibit AC6 activity, which is also expressed at a high level. Thus, during the early stages of pregnancy, when it is important to maintain a relaxed state of myometrium, the alpha 2A-AR activation augments the effect of isoproterenol on the cellular cAMP concentration, promoting smooth muscle relaxation. This effect is probably mediated through Gbeta gamma activation of AC2. At the later stage of pregnancy, when contraction is important, alpha 2-AR inhibits the stimulation of AC by the beta -AR agonists. Marjamaki et al. (101) have proposed that such a switch in the consequences of alpha 2-AR stimulation could be explained by a change in the phosphorylation status of AC2.

cAMP and Drug Dependence

Acute administration of morphine or opioids causes a decrease of AC activity via the Gi pathway, and chronic administration leads to the classic states of tolerance and dependence (122). Dependence includes behavioral and physical signs, behind which is a complex array of biochemical phenomena. Among the various mechanisms underlying these phenomena, one of the most studied since the early work of Sharma et al. (141) on NG 108-15 cells is an upregulation of the cAMP system, including AC, PKA, and the transcriptional factor CREB. Thus, after a long-term in vivo morphine treatment followed by administration of the antagonist naloxone, an increase in the AC activity in the cerebral cortex (45, 98) and in striatum (105, 164) but not in the cerebellum devoid of receptor can be observed. For example, after morphine withdrawal, there is a 30% increase in basal and forskolin-stimulated AC activity in the striatum, an increase that is no longer seen in µ receptor-deficient animals (105). It is also noteworthy that, in an extensive study of the critical role of cAMP in morphine dependence in the rat, Lane-Ladd et al. (87) found an increase in AC1, AC8, PKA, and CREB in the locus coeruleus, a major site responsible for the physical signs of dependence. These data confirm our earlier results on the involvement of AC8 in the locus coeruleus (103).

These changes have been reproduced in various cell culture systems, and one can more or less readily observe an upregulation of AC activity that has the following characteristics: 1) it can be observed after treatment with a variety of inhibitory ligands, including muscarinic agents and somatostatin (167); 2) it is long lived; 3) depending on the system studied, it may or may not involve a transcriptional step (7); 4) the beta gamma -subunits seem to play a specific, although not direct, role (8, 19, 168); and 5) the effect may be specific for certain isoforms of AC (9, 196). Along the same line, it is worth noting that opiates can have bimodal acute effects on cAMP production in the myenteric plexus, depending on the concentration used (177).

Most of the recent results originate from studies involving artificial, transient, or permanent transfections of various AC isoforms. The nature and stoichiometry of the components involved may provide spurious results, and therefore these data should be considered with caution until they can be directly confirmed in better models. However, the upregulation of the AC system is at present the best explanation available for the dependent state after opiate administration.

Interestingly, the recently described model of cannabis withdrawal confirms this model. The recent availability of a specific CB1 antagonist, SR-141716A, has allowed one to set up an in vivo model of cannabis abstinence. After 6 days of treatment with Delta -9 tetrahydrocannabinol, followed by the administration of the antagonist, mice exhibit several somatic signs (wet-dog shakes, facial rubbing, ataxia, hunched posture, mastication) that could be interpreted as being part of a withdrawal syndrome. Interestingly, the same animals exhibit a 100% increase in the basal, forskolin-, and Ca2+/calmodulin-stimulated AC activity in the cerebellum (rich in CB1 receptors) but not in the cortex or the striatum (70).

Alcohol is one of the most widely abused drugs in the world. Although ethanol does not act through a specific receptor, there is increasing evidence that the observed effects result from specific alterations. Among the various biological markers associated with certain subtypes of chronic alcoholism, a low-platelet AC activity has been proposed to reflect a genetic predisposition to alcohol dependence. In most cell culture systems, acute exposure to ethanol treatment has been found to potentiate the receptor-mediated cAMP synthesis. In contrast, chronic exposure often causes a decrease in cAMP production. Parsian et al. (127) have observed that basal and fluoride-stimulated platelet AC activity of alcoholic patients have lower value than in control subjects (127). Moreover, Ikeda et al. (71) have reported that 5'-guanylyl imidodiphosphate- and forskolin-stimulated platelet AC activity may help to distinguish between subtypes of alcoholic patients (those who develop a negative mood in response to drinking, those who continue drinking despite health effects, those who become violent while drinking) (71). Recently, Ratsma et al. (137) have described that the forskolin-stimulated AC activity is considerably lower in platelets of children of alcoholic patients (children who are at high risk for alcoholism but not yet consuming alcohol). Furthermore, the reduced AC activity was only observed in platelets of children from multigenerational family of alcoholism. The platelet AC may therefore represent a trait marker for genetic predisposition to alcoholism.

In human platelets, the major AC isoform expressed is AC7 (67). A selective effect of ethanol on cAMP synthesis through a specific AC isoform has been demonstrated by using HEK-293 cells transfected with different types of ACs: the stimulation of cAMP generation by ethanol was found two- to threefold greater in AC7-transfected cells than in cells transfected with other ACs (197). Recently it has been proposed that ethanol may act by promoting phosphorylation of AC7 (136).

To better understand the mechanism of action of ethanol, animal models have been used. On exposure to ethanol, Drosophila displays behavior quite similar to that observed on ethanol intoxication in rodents and humans. More readily accessible to genetic analysis, Drosophila represents a very attractive model to investigate the molecular mechanisms underlying ethanol dependence. Moore et al. (114) have demonstrated that ethanol intoxication in Drosophila is modulated through the cAMP pathway and probably through AC1 activity (114). Indeed, loss-of-function mutations in rutabaga AC (the Drosophila AC1) increases the sensitivity to ethanol, whereas flies lacking both the cAMP phosphodiesterase (dunce) and the isoform AC1 (rutabaga) are not different from wild-type control flies.


    GENERAL CONCLUSIONS
TOP
ABSTRACT
INTRODUCTION
TISSUE SPECIFICITY OF mRNA...
TRANSCRIPTIONAL REGULATION OF...
POTENTIAL REGULATIONS OF...
FUNCTIONAL RELEVANCE OF...
GENERAL CONCLUSIONS
REFERENCES

The existence of large families of proteins at each level of the cAMP signaling pathways (receptors, G proteins, cyclases, phosphodiesterases) has opened the Pandora's box of combinatorial regulations. No longer can we safely assume that a given hormone will always increase, or decrease, the cAMP content of a cell. We are overwhelmed by the variety of potential regulations of AC activity. Yet, most recent progress in the field of AC has focused on the structural components of the enzymes involved in potential regulations more than on their physiological relevance. For some time, we will probably have to face the usual problem of sorting out important regulatory loops from spurious ones.

In particular, we are still lacking data from knockout experiments with the all various isoforms of AC (only the knockout of AC1 has been reported to date). As cAMP plays a key role during development, conditional knockouts in various organs will be probably necessary. This is all the more needed as a compensatory increase of an isoform to supplement the loss of another one cannot be excluded. From this point of view, it is striking that no pathology linked to the alteration of a cyclase isoform has been reported to far, with the exception of the altered sensory patterning of somatosensory cortex of barrelless mice, whereas the pathology linked to the other components of the cAMP signaling pathway (receptors, G protein) is well known.

Therefore, some of the questions that are likely to be crucial in the years to come might be the following. 1) To what extent are the various isoforms redundant? 2) To what extent are the various cross-talks, potentially regulating cAMP formation, really physiological? For example, if the pineal gland is a good model for AC1 being a potential coincidence detector (for Gsalpha and calmodulin/Ca2+), we have to admit that we have no direct experimental evidence for it. Similarly, the potential inhibition of AC5 and AC6 by Ca2+ is still in need of a convincing demonstration. 3) In the cascade "receptor-G protein-effector," AC is probably limiting, as demonstrated by Post et al. (131) in various systems. However, is the likely cellular compartmentalization of AC interferring with the stoichiometry of the enzyme with respect to the other components? 4) Are the overexpressed, extraneous isoforms localized in the correct compartments? 5) To what extent is the demonstration that the cAMP signaling cascade occurring within a restricted, caveolin-enriched, microdomain of the plasma membrane (140), a constant phenomenon? 6) Are there endogenous analogs of forskolin or adenine nucleoside polyphosphate (39, 77) that could further regulate the activities of the different isoforms?


    ACKNOWLEDGEMENTS

This work has been supported by Institut National de la Santé et de la Recherche Médicale, the University Paris-Val de Marne, the Fondation de France, the Caisse Nationale d'Assurance Maladie, the Fondation Retina France, and the Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie.


    FOOTNOTES

Address for reprint requests and other correspondence: J. Hanoune, Institut National de la Santé et de la Recherche Médicale U-99 Hôpital Henri Mondor, F-94010 Créteil, France (E-mail: hanoune{at}im3.inserm.fr).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
TISSUE SPECIFICITY OF mRNA...
TRANSCRIPTIONAL REGULATION OF...
POTENTIAL REGULATIONS OF...
FUNCTIONAL RELEVANCE OF...
GENERAL CONCLUSIONS
REFERENCES

1.   Abdel-Halim, SM, Guenifi A, He B, Yang B, Mustafa M, Hojeberg B, Hillert J, Bakhiet M, and Efendic S. Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes. Diabetes 47: 498-504, 1998[Abstract].

2.   Abdel-Majid, RM, Leong WL, Schalkwyk LC, Smallman DS, Wong ST, Storm DR, Fine A, Dobson MJ, Guernsey DL, and Neumann PE. Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex. Nature Genet 19: 289-291, 1998[ISI][Medline].

3.   Adamo, S, Conti M, Geremia R, and Monesi V. Particulate and soluble adenylate cyclase activities of mouse male germ cells. Biochem Biophys Res Commun 97: 607-613, 1980[ISI][Medline].

4.   Antoni, FA, Barnard RJ, Shipston MJ, Smith SM, Simpson J, and Paterson JM. Calcineurin feedback inhibition of agonist-evoked cAMP formation. J Biol Chem 270: 28055-28061, 1995[Abstract/Free Full Text].

5.   Antoni, FA, Palkovits M, Simpson J, Smith SM, Leitch AL, Rosie R, Fink G, and Paterson JM. Ca2+/calcineurin-inhibited adenylyl cyclase, highly abundant in forebrain regions, is important for learning and memory. J Neurosci 18: 9650-9661, 1998[Abstract/Free Full Text].

6.   Antoni, FA, Smith SM, Simpson J, Rosie R, Fink G, and Paterson JM. Calcium control of adenylyl cyclase: the calcineurin connection. Adv Second Messenger Phosphoprotein Res 32: 153-172, 1998[Medline].

7.   Avidor-Reiss, T, Bayewitch M, Levy R, Matus-Leibovitch N, Nevo I, and Vogel Z. Adenylyl cyclase supersensitization in µ-opiod receptor-transfected chinese hamster ovary cells following chronic opioid treatment. J Biol Chem 270: 29732-29738, 1995[Abstract/Free Full Text].

8.   Avidor-Reiss, T, Nevo I, Levy R, Pfeuffer T, and Vogel Z. Chronic opioid treatment induces adenylyl cyclase V superactivation-involvement of Gbeta gamma . J Biol Chem 271: 21309-21315, 1996[Abstract/Free Full Text].

9.   Avidor-Reiss, T, Nevo I, Saya D, Bayewitch M, and Vogel Z. Opiate-induced adenylyl cyclase superactivation is isozyme-specific. J Biol Chem 272: 5040-5047, 1997[Abstract/Free Full Text].

10.   Bakalyar, HA, and Reed RR. Identification of a specialized adenylyl cyclase that may mediate odorant detection. Science 250: 1403-1406, 1990[ISI][Medline].

11.   Bayewitch, ML, Avidor-Reiss T, Levy R, Pfeuffer T, Nevo I, Simonds WF, and Vogel Z. Differential modulation of adenylyl cyclases I and II by various Gbeta subunits. J Biol Chem 273: 2273-2276, 1998[Abstract/Free Full Text].

12.   Bayewitch, ML, Avidor-Reiss T, Levy R, Pfeuffer T, Nevo I, Simonds WF, and Vogel Z. Inhibition of adenylyl cyclase isoforms V and VI by various Gbeta gamma subunits. Faseb J 12: 1019-1025, 1998[Abstract/Free Full Text].

13.   Berger, AJ, Hart AC, and Kaplan JM. Galpha s-induced neurodegeneration in Caenorhabditis elegans. J Neurosci 18: 2871-2880, 1998[Abstract/Free Full Text].

14.   Buck, J, Sinclair ML, Schapal L, Cann MJ, and Levin LR. Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals. Proc Natl Acad Sci USA 96: 79-84, 1999[Abstract/Free Full Text].

15.   Bygrave, FL, and Roberts HR. Regulation of cellular calcium through signaling cross-talk involves an intricate interplay between the actions of receptors, G-proteins, and second messengers. FASEB J 9: 1297-1303, 1995[Abstract/Free Full Text].

16.   Cali, JJ, Zwaagstra JC, Mons N, Cooper DM, and Krupinski J. Type VIII adenylyl cyclase. A Ca2+/calmodulin-stimulated enzyme expressed in discrete regions of rat brain. J Biol Chem 269: 12190-12195, 1994[Abstract/Free Full Text].

17.   Casavola, V, Guerra L, Reshkin SJ, Jacobson KA, Verrey F, and Murer H. Effect of adenosine on Na+ and Cl- currents in A6 monolayers. Receptor localization and messenger involvement. J Membr Biol 151: 237-245, 1996[ISI][Medline].

18.   Chabardes, D, Firsov D, Aarab L, Clabecq A, Bellanger AC, Siaume-Perez S, and Elalouf JM. Localization of mRNAs encoding Ca2+-inhibitable adenylyl cyclases along the renal tubule. Functional consequences for regulation of the cAMP content. J Biol Chem 271: 19264-19271, 1996[Abstract/Free Full Text].

19.   Chakrabarti, S, Rivera M, Yan SZ, Tang WJ, and Gintzler AR. Chronic morphine augments Gbeta gamma /Gsalpha stimulation of adenylyl cyclase: relevance to opioid tolerance. Mol Pharmacol 54: 655-662, 1998[Abstract/Free Full Text].

20.   Chaudhry, A, Muffler LA, Yao R, and Granneman JG. Perinatal expression of adenylyl cyclase subtypes in rat brown adipose tissue. Am J Physiol Regulatory Integrative Comp Physiol 270: R755-R760, 1996[Abstract/Free Full Text].

21.   Chen, CJ, Barnett JV, Congo DA, and Brown EM. Divalent cations suppress 3',5'-adenosine monophosphate accumulation by stimulating a pertussis toxin-sensitive guanine nucleotide-binding protein in cultured bovine parathyroid cells. Endocrinology 124: 233-239, 1989[Abstract].

22.   Chen, J, and Iyengar R. Inhibition of cloned adenylyl cyclases by mutant-activated Gi-alpha and specific suppression of type 2 adenylyl cyclase inhibition by phorbol ester treatment. J Biol Chem 268: 12253-12256, 1993[Abstract/Free Full Text].

23.   Chen, J, and Iyengar R. Suppression of Ras-induced transformation of NIH 3T3 cells by activated Galpha s. Science 263: 1278-1281, 1994[ISI][Medline].

24.   Chen, Y, Harry A, Li J, Smit MJ, Bai X, Magnusson R, Pieroni JP, Weng G, and Iyengar R. Adenylyl cyclase 6 is selectively regulated by protein kinase A phosphorylation in a region involved in Galpha s stimulation. Proc Natl Acad Sci USA 94: 14100-14104, 1997[Abstract/Free Full Text].

25.   Chen, Z, Nield HS, Sun H, Barbier A, and Patel TB. Expression of type V adenylyl cyclase is required for epidermal growth factor-mediated stimulation of cAMP accumulation. J Biol Chem 270: 27525-27530, 1995[Abstract/Free Full Text].

26.   Chiono, M, Mahey R, Tate G, and Cooper DM. Capacitative Ca2+ entry exclusively inhibits cAMP synthesis in C6-2B glioma cells. Evidence that physiologically evoked Ca2+ entry regulates Ca(2+)-inhibitable adenylyl cyclase in non-excitable cells. J Biol Chem 270: 1149-1155, 1995[Abstract/Free Full Text].

27.   Choi, EJ, Wong ST, Dittman AH, and Storm DR. Phorbol ester stimulation of the type I and type III adenylyl cyclases in the whole cells. Biochemistry 32: 1891-1894, 1993[ISI][Medline].

28.   Choi, E-J, Xia Z, and Storm DR. Stimulation of the type 3 olfactory adenylyl cyclase by calcium and calmodulin. Biochemistry 31: 6492-6498, 1992[ISI][Medline].

29.   Cohen-Tannoudji, J, Vivat V, Heilman J, Legrand C, and Maltier JP. Regulation by progesterone of the high-affinity state of myometrial beta -adrenergic receptor and of adenylate cyclase activity in the pregnant rat. J Mol Endocrinol 6: 137-145, 1991[Abstract].

30.   Cooper, DM, Karpen JW, Fagan KA, and Mons NE. Ca(2+)-sensitive adenylyl cyclases. Adv Second Messenger Phosphoprotein Res 32: 23-51, 1998[Medline].

31.   Cooper, DM, Mons N, and Fagan K. Ca2+-sensitive adenylyl cyclases. Cell Signal 6: 823-840, 1994[ISI][Medline].

32.   Cooper, DM, Mons N, and Karpen JW. Adenylyl cyclases and the interaction between calcium and cAMP signalling. Nature 374: 421-424, 1995[ISI][Medline].

33.   Cooper, DM, Yoshimura M, Zhang Y, Chiono M, and Mahey R. Capacitative Ca2+ entry regulates Ca(2+)-sensitive adenylyl cyclases. Biochem J 297: 437-440, 1994[ISI][Medline].

34.   Debernardi, MA, Munshi R, Yoshimura M, Cooper DM, and Brooker G. Predominant expression of type-VI adenylate cyclase in C6-2B rat glioma cells may account for inhibition of cyclic AMP accumulation by calcium. Biochem J 293: 325-328, 1993[ISI][Medline].

35.   Defer, N, Marinx O, Poyard M, Lienard MO, Jegou B, and Hanoune J. The olfactory adenylyl cyclase type 3 is expressed in male germ cells. FEBS Lett 424: 216-220, 1998[ISI][Medline].

36.   Defer, N, Marinx O, Stengel D, Danisova A, Iourgenko V, Matsuoka I, Caput D, and Hanoune J. Molecular cloning of the human type VIII adenylyl cyclase. FEBS Lett 351: 109-113, 1994[ISI][Medline].

37.   De Jesus Ferreira, MC, Helies-Toussaint C, Imbert-Teboul M, Bailly C, Verbavatz JM, Bellanger AC, and Chabardes D. Co-expression of a Ca2+-inhibitable adenylyl cyclase and of a Ca2+-sensing receptor in the cortical thick ascending limb cell of the rat kidney. Inhibition of hormone-dependent cAMP accumulation by extracellular Ca2+. J Biol Chem 273: 15192-15202, 1998[Abstract/Free Full Text].

38.   De Rooij, J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, and Bos JL. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396: 474-477, 1998[ISI][Medline].

39.   Desaubry, L, and Johnson RA. Adenine nucleoside 3'-tetraphosphates are novel and potent inhibitors of adenylyl cyclases. J Biol Chem 273: 24972-24977, 1998[Abstract/Free Full Text].

40.   Dessauer, CM, and Gilman AG. Purification and characterization of a soluble form of mammalian adenylyl cyclase. J Biol Chem 271: 16967-16974, 1996[Abstract/Free Full Text].

41.   Dessauer, CW, Scully TT, and Gilman AG. Interactions of forskolin and ATP with the cytosolic domains of mammalian adenylyl cyclase. J Biol Chem 272: 22272-22277, 1997[Abstract/Free Full Text].

42.   Dessauer, CW, Tesmer JJ, Sprang SR, and Gilman AG. Identification of a Gialpha binding site on type V adenylyl cyclase. J Biol Chem 273: 25831-25839, 1998[Abstract/Free Full Text].

43.   Dudai, Y, and Zvi S. Adenylate cyclase in the Drosophila memory mutant rutabaga displays an altered Ca2+ sensitivity. Neurosci Lett 47: 119-124, 1984[ISI][Medline].

44.   Dudai, Y, and Zvi S. Multiple effect of the activity of adenylyl cyclase from the Drosophila memory mutant rutabaga. J Neurochem 45: 355-364, 1985[ISI][Medline].

45.   Duman, RS, Tallman JF, and Nestler EJ. Acute and chronic opiate-regulation of adenylate cyclase in brain: specific effects in locus coeruleus. J Pharmacol Exp Ther 246: 1033-1039, 1988[Abstract].

46.   Dumont, JE, Jauniaux JC, and Roger PP. The cyclic AMP-mediated stimulation of cell proliferation. Trends Biochem Sci 14: 67-71, 1989[ISI][Medline].

47.   Ebina, T, Kawabe J, Katada T, Ohno S, Homcy CJ, and Ishikawa Y. Conformation-dependent activation of type II adenylyl cyclase by protein kinase C. J Cell Biochem 64: 492-498, 1997[ISI][Medline].

48.   Ecelbarger, CA, Yu S, Lee AJ, Weinstein LS, and Knepper MA. Decreased renal Na-K-2Cl cotransporter abundance in mice with heterozygous disruption of the G(s)alpha gene. Am J Physiol Renal Physiol 277: F235-F244, 1999[Abstract/Free Full Text].

49.   Edelhoff, S, Villacres EC, Storm DR, and Disteche CM. Mapping of the adenylyl cyclase genes type I, II, III, IV, V, and VI in mouse. Mamm Genome 6: 111-113, 1995[ISI][Medline].

50.   Elwardy-Merezak, J, Maltier JP, Cohen-Tannoudji J, Lecrivain JL, Vivat V, and Legrand C. Pregnancy-related modifications of rat myometrial Gs proteins: ADP ribosylation, immunoreactivity and gene expression studies. J Mol Endocrinol 13: 23-27, 1994[Abstract].

51.   Emala, CW, Kumasaka D, Hirshman CA, and Lindeman KS. Adenylyl cyclase messenger ribonucleic acid in myometrium: splice variant of type IV. Biol Reprod 59: 169-175, 1998[Abstract/Free Full Text].

52.   Espinasse, I, Iourgenko V, Defer N, Samson F, Hanoune J, and Mercadier JJ. Type V, but not type VI adenylyl cyclase mRNA accumulates in the heart during ontogenic development. Correlation with adenylyl cyclase activity. J Mol Cardiol 27: 1789-1795, 1995[ISI][Medline].

53.   Federman, AD, Conklin BR, Schrader KA, Reed RR, and Bourne HR. Hormonal stimulation of adenylate cyclase through Gi-protein beta gamma subunits. Nature 356: 159-161, 1992[ISI][Medline].

54.   Furuyama, T, Inagaki S, and Takagi H. Distribution of the type II adenylyl cyclase in the rat brain. Brain Res Mol Brain Res 19: 165-170, 1993[ISI][Medline].

55.   Gao, BN, and Gilman AG. Cloning and expression of a widely distributed (type IV) adenylyl cyclase. Proc Natl Acad Sci USA 88: 10178-10182, 1991[Abstract].

56.   Gao, T, Puri TS, Gerhardstein BL, Chien AJ, Green RD, and Hosey MM. Identification and subcellular localization of the subunits of L-type calcium channels and adenylyl cyclase in cardiac myocytes. J Biol Chem 272: 19401-19407, 1997[Abstract/Free Full Text].

57.   Gautier-Courteille, C, Salanova M, and Conti M. The olfactory adenylyl cyclase III is expressed in rat germ cells during spermiogenesis. Endocrinology 139: 2588-2599, 1998[Abstract/Free Full Text].

58.   Granneman, JG. Expression of adenylyl cyclase subtypes in Brown adipose tissues: neural regulation of type III. Endocrinology 136: 2007-2012, 1995[Abstract].

59.   Gu, C, and Cooper DM. Calmodulin-binding sites on adenylyl cyclase type VIII. J. Biol Chem 274: 8012-8021, 1999[Abstract/Free Full Text].

60.   Haber, N, Stengel D, Defer N, Roeckel N, Mattei-G M, and Hanoune J. Chromosomal mapping of human adenylyl cyclase genes type III, type V and type VI. Hum Genet 94: 69-73, 1994[ISI][Medline].

61.   Hacker, BM, Tomlinson JE, Wayman GA, Sultana R, Chan G, Villacres E, Disteche C, and Storm DR. Cloning, chromosomal mapping, and regulatory properties of the human type 9 adenylyl cyclase (ADCY9). Genomics 50: 97-104, 1998[ISI][Medline].

62.   Hafner, S, Adler HS, Mischak H, Janosch P, Heidecker G, Wolfman A, Pippig S, Lohse M, Ueffing M, and Kolch W. Mechanism of inhibition of Raf-1 by protein kinase A. Mol Cell Biol 14: 6696-6703, 1994[Abstract].

63.   Hanoune, J, Pouille Y, Tzavara E, Shen T, Lipskaya L, Miyamoto N, Suzuki Y, and Defer N. Adenylyl cyclases: structure, regulation and function in an enzyme superfamily. Mol Cell Endocrinol 128: 179-194, 1997[ISI][Medline].

64.   Hanson, AS, and Linas SL. beta -Adrenergic receptor function in rat proximal tubule epithelial cells in culture. Am J Physiol Renal Fluid Electrolyte Physiol 268: F553-F560, 1995[Abstract/Free Full Text].

65.   Harry, A, Chen Y, Magnusson R, Iyengar R, and Weng G. Differential regulation of adenylyl cyclases by Galpha s. J Biol Chem 272: 19017-19021, 1997[Abstract/Free Full Text].

66.   Hellevuo, K, Berry R, Sikela JM, and Tabakoff B. Localization of the gene for a novel human adenylyl cyclase (ADCY7) to chromosome 16. Hum Genet 95: 197-200, 1995[ISI][Medline].

67.   Hellevuo, K, Yoshimura M, Mons N, Hoffman PL, Cooper DM, and Tabakoff B. The characterization of a novel human adenylyl cyclase which is present in brain and other tissues. J Biol Chem 270: 11581-11589, 1995[Abstract/Free Full Text].

68.   Huang, L, Wei YY, Momose-Hotokezaka A, Dickey J, and Okusa MD. alpha 2B-Adrenergic receptors: immunolocalization and regulation by potassium depletion in rat kidney. Am J Physiol Renal Fluid Electrolyte Physiol 270: F1015-F1026, 1996[Abstract/Free Full Text].

69.   Hurley, JH. Structure, mechanism, and regulation of mammalian adenylyl cyclase. J Biol Chem 274: 7599-7602, 1999[Free Full Text].

70.   Hutcheson, DM, Tzavara ET, Smadja C, Valjent E, Roques BP, Hanoune J, and Maldonado R. Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol. Br J Pharmacol 125: 1567-1577, 1998[Abstract].

71.   Ikeda, H, Menninger JA, and Tabakoff B. An initial study of the relationship between platelet adenylyl cyclase activity and alcohol use disorder criteria. Alcohol Clin Exp Res 22: 1057-1064, 1998[ISI][Medline].

72.   Iourgenko, V, Kliot B, Cann MJ, and Levin LR. Cloning and characterization of a Drosophila adenylyl cyclase homologous to mammalian type IX. FEBS Lett 413: 104-108, 1997[ISI][Medline].

73.   Ishikawa, Y, Katsushika S, Chen L, Halnon NJ, Kawabe-I J, and Homcy CJ. Isolation and characterization of a novel cardiac adenylylcyclase cDNA. J Biol Chem 267: 13553-13557, 1992[Abstract/Free Full Text].

74.   Iwami, G, Kawabe J, Ebina T, Cannon PJ, Homcy CJ, and Ishikawa Y. Regulation of adenylyl cyclase by protein kinase A. J Biol Chem 270: 12481-12484, 1995[Abstract/Free Full Text].

75.   Iyengar, R. Molecular and functional diversity of mammalian Gs-stimulated adenylyl cyclases. FASEB J 7: 768-775, 1993[Abstract/Free Full Text].

76.   Jacobowitz, O, Chen J, Premont RT, and Iyengar R. Stimulation of specific types of Gs-stimulated adenylyl cyclases by phorbol ester treatment. J Biol Chem 268: 3829-3832, 1993[Abstract/Free Full Text].

77.   Johnson, RA, Desaubry L, Bianchi G, Shoshani I, Lyons E, Jr, Taussig R, Watson PA, Cali JJ, Krupinski J, Pieroni JP, and Iyengar R. Isozyme-dependent sensitivity of adenylyl cyclases to P-site-mediated inhibition by adenine nucleosides and nucleoside 3'-polyphosphates. J Biol Chem 272: 8962-8966, 1997[Abstract/Free Full Text].

78.   Jones, DT, and Reed RR. Golf: an olfactory neuron specific-G protein involved in odorant signal transduction. Science 244: 790-795, 1989[ISI][Medline].

79.   Kawabe, J, Ebina T, Toya Y, Oka N, Schwencke C, Duzic E, and Ishikawa Y. Regulation of type V adenylyl cyclase by PMA-sensitive and -insensitive protein kinase C isoenzymes in intact cells. FEBS Lett 384: 273-276, 1996[ISI][Medline].

80.   Kawabe, J, Iwami G, Ebina T, Ohno S, Katada T, Ueda Y, Homcy CJ, and Ishikawa Y. Differential activation of adenylyl cyclase by protein kinase C isoenzymes. J Biol Chem 269: 16554-16558, 1994[Abstract/Free Full Text].

81.   Kawasaki, H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, and Graybiel AM. A family of cAMP-binding proteins that directly activate Rap1. Science 282: 2275-2279, 1998[Abstract/Free Full Text].

82.   Kifor, O, Diaz R, Butters R, and Brown EM. The Ca2+-sensing receptor (CaR) activates phospholipases C, A2, and D in bovine parathyroid and CaR-transfected, human embryonic kidney (HEK293) cells. J Bone Miner Res 12: 715-725, 1997[ISI][Medline].

83.   Kornblihtt, AR, Flawia MM, and Torres HN. Manganese ion dependent adenylate cyclase activity in rat testes: purification and properties. Biochemistry 20: 1262-1267, 1981[ISI][Medline].

84.   Korswagen, HC, van der Linden AM, and Plasterk RH. G protein hyperactivation of the Caenorhabditis elegans adenylyl cyclase SGS-1 induces neuronal degeneration. EMBO J 17: 5059-5065, 1998[Abstract/Free Full Text].

85.   Kozasa, T, and Gilman AG. Purification of recombinant G proteins from Sf9 cells by hexahistidine tagging of associated subunits. Characterization of alpha 12 and inhibition of adenylyl cyclase by alpha z. J Biol Chem 270: 1734-1741, 1995[Abstract/Free Full Text].

86.   Krupinski, J, Coussen F, Balkayar HA, Tang W-J, Feinstein PG, Orth K, Slaughter C, Reed RR, and Gilman AG. Adenylyl cyclase amino acid sequence: possible channel- or transporter-like structure. Science 244: 1558-1564, 1989[ISI][Medline].

87.   Lane-Ladd, SB, Pineda J, Boundy VA, Pfeuffer T, Krupinski J, Aghajanian GK, and Nestler EJ. CREB (cAMP response element-binding protein) in the locus coeruleus: biochemical, physiological, and behavioral evidence for a role in opiate dependence. J Neurosci 17: 7890-7901, 1997[Abstract/Free Full Text].

88.   Legssyer, A, Poggioli J, Renard D, and Vassort G. ATP and other adenine compounds increase mechanical activity and inositol trisphosphate production in rat heart. J Physiol (Lond) 401: 185-199, 1988[Abstract].

89.   Levin, LR, Han PL, Hwang PM, Feinstein PG, Davis RL, and Reed RR. The Drosophila learning and memory gene rutabaga encodes a Ca2+/calmodulin-responsive adenylyl cyclase. Cell 68: 479-489, 1992[ISI][Medline].

90.   Levin, LR, and Reed RR. Identification of functional domains of adenylyl cyclase using in vivo chimeras. J Biol Chem 270: 7573-7579, 1995[Abstract/Free Full Text].

91.   Levy-Toledano, R, Blaettler DH, LaRochelle WJ, and Taylor SI. Insulin-induced activation of phosphatidylinositol (PI) 3-kinase. Insulin-induced phosphorylation of insulin receptors and insulin receptor substrate-1 displaces phosphorylated platelet-derived growth factor receptors from binding sites on PI 3-kinase. J Biol Chem 270: 30018-30022, 1995[Abstract/Free Full Text].

91a.   Lipskaia, L, Defer N, Esposito G, Hajar I, Garel MC, Rockman HA, and Hanoune J. Enhanced cardiac function in transgenic mice expressing a Ca(2+)-stimulated adenylyl cyclase. Circ Res 86: 795-801, 2000[Abstract/Free Full Text].

92.   Lipskaia, L, Djiane A, Defer N, and Hanoune J. Different expression of adenylyl cyclase isoforms after retinoic acid induction of P19 teratocarcinoma cells. FEBS Lett 415: 275-280, 1997[ISI][Medline].

93.   Lipskaia, L, Grepin C, Defer N, and Hanoune J. Adenylyl cyclase activity and gene expression during mesodermal differentiation of the P19 embryonal carcinoma cells. J Cell Physiol 176: 50-56, 1998[ISI][Medline].

94.   Livingstone, MS, Sziber PP, and Quinn WG. Loss of calcium/calmodulin responsiveness in adenylate cyclase of rutabaga, a Drosophila learning mutant. Cell 37: 205-215, 1984[ISI][Medline].

95.   Lustig, KD, Conklin BR, Herzmark P, Taussig R, and Bourne HR. Type II adenylyl cyclase integrates coincident signals from Gs, Gi, and Gq. J Biol Chem 268: 13900-13905, 1993[Abstract/Free Full Text].

96.   Ma, H, and Ling BN. Luminal adenosine receptors regulate amiloride-sensitive Na+ channels in A6 distal nephron cells. Am J Physiol Renal Fluid Electrolyte Physiol 270: F798-F805, 1996[Abstract/Free Full Text].

97.   Magnaldo, I, Pouyssegur J, and Paris S. Cyclic AMP inhibits mitogen-induced DNA synthesis in hamster fibroblasts, regardless of the signalling pathway involved. FEBS Lett 245: 65-69, 1989[ISI][Medline].

98.   Maldonado, R, Blendy JA, Tzavara E, Gass P, Roques BP, Hanoune J, and Schutz G. Reduction of morphine abstinence in mice with a mutation in the gene encoding CREB. Science 273: 657-659, 1996[Abstract].

99.   Maltier, JP, Bengham-Eyéné Y, and Legrand C. Regulation of myometrial beta 2-adrenergic receptors by progesterone and estradiol-17beta in late pregnant rat. Biol Reprod 40: 531-540, 1989[Abstract].

100.   Mamluk, R, Defer N, Hanoune J, and Meidan R. Molecular identification of adenylyl cyclase 3 in bovine corpus luteum and its regulation by prostaglandin F2alpha - induced signaling pathway. Endocrinology 140: 4601-4608, 1999[Abstract/Free Full Text].

101.   Marjamaki, A, Sato M, Bouet-Alard R, Yang Q, Limon-Boulez I, Legrand C, and Lanier SM. Factors determining the specificity of signal transduction by guanine nucleotide-binding protein-coupled receptors. Integration of stimulatory and inhibitory input to the effector adenylyl cyclase. J Biol Chem 272: 16466-16473, 1997[Abstract/Free Full Text].

102.   Matsuoka, I, Giuili G, Poyard M, Stengel D, Parma J, Guellaen G, and Hanoune J. Localization of adenylyl and guanylyl cyclase in rat brain by in situ hybridization: Comparison with calmodulin mRNA distribution. J Neuroscience 12: 3350-3360, 1992[Abstract].

103.   Matsuoka, I, Maldonado R, Defer N, Noel F, Hanoune J, and Rocques B. Chronic morphine administration causes region-specific increase of brain type VIII adenylyl cyclase mRNA. Eur J Pharmacol 268: 215-221, 1994[Medline].

104.   Matsuoka, I, Suzuki Y, Defer N, Nakashini H, and Hanoune J. Differential expression of type I, II, and V adenylyl cyclase gene in the postnatal developing rat brain. J Neurochem 68: 498-506, 1997[ISI][Medline].

105.   Matthes, HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dolle P, Tzavara E, Hanoune J, Roques BP, and Kieffer BL. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene. Nature 383: 819-823, 1996[ISI][Medline].

106.   McBurney, MW, Jones-Villeneuve EMV, Edwards MKS, and Anderson PJ. Controlled differentiation and maturation of teratocarcinoma cells in culture. Nature 299: 165-167, 1982[ISI][Medline].

107.   Menco, BPM, Bruch RC, Dau B, and Danho W. Ultrastructural localization of olfactory transduction components: the G protein subunit Golf and type III adenylyl cyclase. Neuron 8: 441-453, 1992[ISI][Medline].

108.   Mhaouty, S, Cohen-Tannoudji J, Bouet-Alard R, Limon-Boulez I, Maltier JP, and Legrand C. Characteristics of the alpha 2/beta 2-adrenergic receptor-coupled adenylyl cyclase system in rat myometrium during pregnancy. J Biol Chem 270: 11012-11016, 1995[Abstract/Free Full Text].

109.   Mhaouty-Kodja, S, Bouet-Alard R, Limon-Boulez I, Maltier JP, and Legrand C. Molecular diversity of adenylyl cyclases in human and rat myometrium. Correlation with global adenylyl cyclase activity during mid- and term pregnancy. J Biol Chem 272: 31100-31106, 1997[Abstract/Free Full Text].

110.   Mons, N, and Cooper DM. Adenylyl cyclase mRNA expression does not reflect the predominant Ca2+/calmodulin-stimulated activity in the hypothalamus. J Neuroendocrinol 6: 665-671, 1994[ISI][Medline].

111.   Mons, N, and Cooper DM. Selective expression of one Ca2+-inhibitable adenylyl cyclase in dopaminergically innervated rat brain regions. Brain Res Mol Brain Res 22: 236-244, 1994[ISI][Medline].

112.   Mons, N, Harry A, Dubourg P, Premont RT, Iyengar R, and Cooper DM. Immunohistochemical localization of adenylyl cyclase in rat brain indicates a highly selective concentration in synapses. Proc Natl Acad Sci USA 92: 8473-8477, 1995[Abstract].

113.   Mons, N, Yoshimura M, and Cooper DMF Discrete expression of Ca2+/calmodulin-sensitive and Ca2+-insensitive adenylyl cyclases in the rat brain. Synapse 14: 51-59, 1993[ISI][Medline].

114.   Moore, MS, DeZazzo J, Luk AY, Tully T, Singh CM, and Heberlein U. Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathway. Cell 93: 997-1007, 1998[ISI][Medline].

115.   Muglia, LM, Schaefer ML, Vogt SK, Gurtner G, Imamura A, and Muglia LJ. The 5'-flanking region of the mouse adenylyl cyclase type VIII gene imparts tissue-specific expression in transgenic mice. J Neurosci 19: 2051-2058, 1999[Abstract/Free Full Text].

116.   Murthy, KS, and Makhlouf GM. Regulation of adenylyl cyclase type V/VI in smooth muscle: interplay of inhibitory G protein and Ca2+ influx. Mol Pharmacol 54: 122-128, 1998[Abstract/Free Full Text].

117.   Nair, BG, and Patel TB. Regulation of cardiac adenylyl cyclase by epidermal growth factor (EGF). Role of EGF receptor protein tyrosine kinase activity. Biochem Pharmacol 46: 1239-1245, 1993[ISI][Medline].

118.   Nair, BG, Rashed HM, and Patel TB. Epidermal growth factor produces inotropic and chronotropic effects in rat hearts by increasing cyclic AMP accumulation. Growth Factors 8: 41-48, 1993[ISI][Medline].

119.   Nair, BG, Rashed HM, and Patel TB. Epidermal growth factor stimulates rat cardiac adenylate cyclase through a GTP-binding regulatory protein. Biochem J 264: 563-571, 1989[ISI][Medline].

120.   Nakanishi, H, Brewer KA, and Exton JH. Activation of the zeta  isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 268: 13-16, 1993[Abstract/Free Full Text].

121.   Neer, E. Physical and functional properties of adenylate cyclase from mature rat testis. J Biol Chem 253: 5808-5812, 1978[Abstract].

122.   Nestler, EJ. Molecular mechanisms of drug addiction. J Neurosci 12: 2439-2450, 1992[ISI][Medline].

123.   Okusa, MD, Huang L, Momose-Hotokezaka A, Huynh LP, and Mangrum AJ. Regulation of adenylyl cyclase in polarized renal epithelial cells by G protein-coupled receptors. Am J Physiol Renal Physiol 273: F883-F891, 1997[Abstract/Free Full Text].

124.   Olianas, MC, and Onali P. GABA(B) receptor-mediated stimulation of adenylyl cyclase activity in membranes of rat olfactory bulb. Br J Pharmacol 126: 657-664, 1999[Abstract/Free Full Text].

125.   Olianas, MC, and Onali P. Mediation by G protein beta gamma subunits of the opioid stimulation of adenylyl cyclase activity in rat olfactory bulb. Biochem Pharmacol 57: 649-652, 1999[ISI][Medline].

126.   Otte, AP, van Run P, Heideveld M, van Driel R, and Durston AJ. Neural induction is mediated by cross-talk between the protein kinase C and cyclic AMP pathways. Cell 58: 641-648, 1989[ISI][Medline].

127.   Parsian, A, Todd RD, Cloninger CR, Hoffman PL, Ovchinnikova L, Ikeda H, and Tabakoff B. Platelet adenylyl cyclase activity in alcoholics and subtypes of alcoholics. WHO/ISBRA Study Clin Centers Alcohol Clin Exp Res 20: 745-751, 1996.

128.   Paterson, JM, Smith SM, Harmar AJ, and Antoni FA. Control of a novel adenylyl cyclase by calcineurin. Biochem Biophys Res Commun 214: 1000-1008, 1995[ISI][Medline].

129.   Pieroni, JP, Harry A, Chen J, Jacobowitz O, Magnusson RP, and Iyengar R. Distinct characteristics of the basal activities of adenylyl cyclases 2 and 6. J Biol Chem 270: 21368-21373, 1995[Abstract/Free Full Text].

130.   Pitt, GS, Milona N, Borleis J, Lin KC, Reed RR, and Devreotes PN. Structurally distinct and stage-specific adenylyl cyclase genes play different roles in Dictyostelium development. Cell 69: 305-315, 1992[ISI][Medline].

131.   Post, SR, Hilal-Dandan R, Urasawa K, Brunton LL, and Insel PA. Quantification of signalling components and amplification in the beta -adrenergic-receptor-adenylate cyclase pathway in isolated adult rat ventricular myocytes. Biochem J 311: 75-80, 1995[ISI][Medline].

132.   Premont, RT, Chen J, Ma-W H, Ponnapalli M, and Iyengar R. Two members of a widely expressed subfamily of hormone-stimulated adenylyl cyclases. Proc Natl Acad Sci USA 89: 9809-9813, 1992[Abstract].

133.   Premont, RT, Jacobowitz O, and Iyengar R. Lowered responsiveness of the catalyst of adenylyl cyclase to stimulation by Gs in heterologous desensitization: a role for adenosine 3', 5'-monophosphate-dependent phosphorylation. Endocrinology 131: 2774-2784, 1992[Abstract].

134.   Premont, RT, Matsuoka I, Mattei MG, Pouille Y, Defer N, and Hanoune J. Identification and characterization of a novel and widely-expressed isoform of adenylyl cyclase. J Biol Chem 271: 13900-13907, 1996[Abstract/Free Full Text].

135.   Puceat, M, Bony C, Jaconi M, and Vassort G. Specific activation of adenylyl cyclase V by a purinergic agonist. FEBS Lett 431: 189-194, 1998[ISI][Medline].

136.   Rabbani, M, Nelson EJ, Hoffman PL, and Tabakoff B. Role of protein kinase C in ethanol-induced activation of adenylyl cyclase. Alcohol Clin Exp Res 23: 77-86, 1999[ISI][Medline].

137.   Ratsma, JE, Gunning WB, Leurs R, and Schoffelmeer AN. Platelet adenylyl cyclase activity as a biochemical trait marker for predisposition to alcoholism. Alcohol Clin Exp Res 23: 600-4, 1999[ISI][Medline].

138.   Rodbell Nobel Lecture M.. Signal transduction: evolution of an idea. Biosci Rep 15: 117-33, 1995[ISI][Medline].

139.   Scholich, K, Barbier AJ, Mullenix JB, and Patel TB. Characterization of soluble forms of nonchimeric type V adenylyl cyclases. Proc Natl Acad Sci USA 94: 2915-2920, 1997[Abstract/Free Full Text].

140.   Schwencke, C, Yamamoto M, Okumura S, Toya Y, Kim SJ, and Ishikawa Y. Compartmentation of cyclic adenosine 3',5'-monophosphate signaling in caveolae. Mol Endocrinol 13: 1061-1070, 1999[Abstract/Free Full Text].

141.   Sharma, SK, Klee WA, and Nirenberg M. Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proc Natl Acad Sci USA 74: 3365-3369, 1975.

142.   Shen, T, Suzuki Y, Poyard M, Best-Belpomme M, Defer N, and Hanoune J. Localization and differential expression of adenylyl cyclase messenger ribonucleic acids in rat adrenal gland determined by in situ hybridization. Endocrinology 138: 4591-4598, 1997[Abstract/Free Full Text].

143.   Shen, T, Suzuki Y, Poyard M, Miyamoto N, Defer N, and Hanoune J. Expression of adenylyl cyclase mRNAs in the adult, in developing, and in the Brattleboro rat kidney. Am J Physiol Cell Physiol 273: C323-C330, 1997[Abstract/Free Full Text].

144.   Shlatz, LJ, Schwartz IL, Kinne-Saffran E, and Kinne R. Distribution of parathyroid hormone-stimulated adenylate cyclase in plasma membranes of cells of the kidney cortex. J Membr Biol 24: 131-144, 1975[ISI][Medline].

145.   Simonds, WF. G protein regulation of adenylate cyclase. Trends Pharmacol Sci 20: 66-73, 1999[ISI][Medline].

146.   Smit, MJ, and Iyengar R. Mammalian adenylyl cyclases. Adv Second Messenger Phosphoprotein Res 32: 1-21, 1998[Medline].

147.   Smit, MJ, Verzijl D, and Iyengar R. Identity of adenylyl cyclase isoform determines the rate of cell cycle progression in NIH 3T3 cells. Proc Natl Acad Sci USA 95: 15084-15089, 1998[Abstract/Free Full Text].

148.   Stengel, D, and Hanoune J. The catalytic subunit of ram sperm adenylate cyclase can be activated through the guanine nucleotide regulatory component and prostaglandin receptors of human erythrocyte. J Biol Chem 256: 5394-5398, 1981[Abstract/Free Full Text].

149.   Stengel, D, Henry D, Tomova S, Borsodi A, and Hanoune J. Purification of the proteolytically solubilized, active catalytic subunit of adenylate cyclase from ram sperm. Inhibition by adenosine. Eur J Biochem 161: 241-247, 1986[Abstract].

150.   Stengel, D, Parma J, Gannage-H M, Roeckel N, Mattei M-G, Barouki R, and Hanoune J. Different chromosomal localization of two adenylyl cyclase genes expressed in human brain. Hum Genet 90: 126-130, 1992[ISI][Medline].

151.   Storm, DR, Hansel C, Hacker B, Parent A, and Linden DJ. Impaired cerebellar long-term potentiation in type I adenylyl cyclase mutant mice. Neuron 20: 1199-210, 1998[ISI][Medline].

152.   Sunahara, RK, Dessauer CW, and Gilman AG. Complexity and diversity of mammalian adenylyl cyclases. Annu Rev Pharmacol Toxicol 36: 461-480, 1996[ISI][Medline].

153.   Suzuki, Y, Shen T, Miyamoto N, Defer N, Matsuoka I, and Hanoune J. Changes in the expression of adenylyl cyclases in the rat uterus during the course of pregnancy. Biol Reprod 57: 778-782, 1997[Abstract].

154.   Suzuki, Y, Shen T, Poyard M, Best-Belpomme M, Hanoune J, and Defer N. Expression of adenylyl cyclase mRNAs in the denervated and in the developing mouse skeletal muscle. Am J Physiol Cell Physiol 274: C1674-C1685, 1998[Abstract/Free Full Text].

155.   Takaichi, K, and Kurokawa K. High Ca2+ inhibits peptide hormone-dependent cAMP production specifically in thick ascending limbs of Henle. Miner Electrolyte Metab 12: 342-346, 1986[ISI][Medline].

156.   Tang, W-J, and Gilman AG. Type-specific regulation of adenylyl cyclase by G protein beta gamma -subunits. Science 254: 1500-1503, 1991[ISI][Medline].

157.   Tang, W-J, and Gilman AG. Construction of a soluble adenylyl cyclase activated by Gsalpha and forskolin. Science 268: 1769-1772, 1995[ISI][Medline].

158.   Tang, W-J, and Hurley JH. Catalytic mechanism and regulation of mammalian adenylyl cyclases. Mol Pharmacol 54: 231-240, 1998[Free Full Text].

159.   Tang, W-J, Krupinski J, and Gilman AG. Expression and characterization of calmodulin-activated (type I) adenylylcyclase. J Biol Chem 266: 8595-8603, 1991[Abstract/Free Full Text].

160.   Taussig, R, and Gilman AG. Mammalian membrane-bound adenylyl cyclases. J Biol Chem 270: 1-4, 1995[Free Full Text].

161.   Taussig, R, Iniguez-Lluhi JA, and Gilman AG. Inhibition of adenylyl cyclase by Gialpha . Science 261: 218-221, 1993[ISI][Medline].

162.   Taussig, R, Quarmby LM, and Gilman AG. Regulation of purified type I and type II adenylyl cyclases by G protein beta gamma subunits. J Biol Chem 268: 9-12, 1993[Abstract/Free Full Text].

163.   Taussig, R, Tang WJ, Hepler JR, and Gilman AG. Distinct patterns of bidirectional regulation of mammalian adenylyl cyclases. J Biol Chem 269: 6093-6100, 1994[Abstract/Free Full Text].

164.   Terwilliger, RZ, Beitner-Johnson D, Sevarino KA, Crain SM, and Nestler EJ. A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res 548: 100-110, 1991[ISI][Medline].

165.   Tesmer, JJ, and Sprang SR. The structure, catalytic mechanism and regulation of adenylyl cyclase. Curr Opin Struct Biol 8: 713-719, 1998[ISI][Medline].

166.   Tesmer, JJ, Sunahara RK, Gilman AG, and Sprang SR. Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha -GTPgamma S. Science 278: 1907-1916, 1997[Abstract/Free Full Text].

167.   Thomas, JM, and Hoffman BB. Adenylate cyclase supersensitivity: a general means of cellular adaptation to inhibitory agonists? Trends Pharmacol Sci 8: 308-311, 1987[ISI].

168.   Thomas, JM, and Hoffman BB. Isoform-specific sensitization of adenylyl cyclase activity by prior activation of inhibitory receptors: role of beta gamma subunits in transducing enhanced activity of the type VI isoform. Mol Pharmacol 49: 907-914, 1996[Abstract].

169.   Tobise, K, Ishikawa Y, Holmer SR, Im-J M, Newell JB, Yoshie H, Fujita M, Susannie EE, and Homcy CJ. Changes in type VI adenylyl cyclase isoform expression correlate with a decreased capacity for cAMP generation in the aging ventricle. Circ Res 74: 596-603, 1994[Abstract].

170.   Tzavara, ET, Pouille Y, Defer N, and Hanoune J. Diurnal variation of the adenylyl cyclase type 1 in the rat pineal gland. Proc Natl Acad Sci USA 93: 11208-11212, 1996[Abstract/Free Full Text].

171.   Villacres, EC, Wong ST, Chavkin C, and Storm DR. Type I adenylyl cyclase mutant mice have impaired mossy fiber long-term potentiation. J Neurosci 18: 3186-3194, 1998[Abstract/Free Full Text].

172.   Villacres, EC, Wu Z, Hua W, Nielsen MD, Watters JJ, Yan C, Beavo J, and Storm DR. Developmentally expressed Ca(2+)-sensitive adenylyl cyclase activity is disrupted in the brains of type I adenylyl cyclase mutant mice. J Biol Chem 270: 14352-14357, 1995[Abstract/Free Full Text].

173.   Villacres, EC, Xia Z, Bookbinder LH, Edelhoff S, Disteche CM, and Storm DR. Cloning, chromosomal mapping, and expression of human fetal brain type I adenylyl cyclase. Genomics 16: 473-478, 1993[ISI][Medline].

174.   Vivat, V, Cohen-Tannoudji J, Revelli JP, Muzzin P, Giacobino JP, Maltier JP, and Legrand C. Progesterone transcriptionally regulates the beta 2-adrenergic receptor gene in pregnant rat myometrium. J Biol Chem 267: 7975-7978, 1992[Abstract/Free Full Text].

175.   Vorherr, T, Knopfel L, Hofmann F, Mollner S, Pfeuffer T, and Carafoli E. The calmodulin binding domain of nitric oxide synthase and adenylyl cyclase. Biochemistry 32: 6081-6088, 1993[ISI][Medline].

176.   Vossler, MR, Yao H, York RD, Pan MG, Rim CS, and Stork PJ. cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89: 73-82, 1997[ISI][Medline].

177.   Wang, L, and Gintzler AR. Bimodal opioid regulation of cyclic AMP formation: implications for positive and negative coupling of opiate receptors to adenylyl cyclase. J Neurochem 63: 1726-1730, 1994[ISI][Medline].

178.   Wang, MM, Tsai RYL, Schrader KA, and Reed RR. Genes encoding components of the olfactory signal transduction cascade contain a DNA binding site that may direct neuronal expression. Mol Cell Biol 13: 5805-5813, 1993[Abstract].

179.   Watson, PA, Krupinski J, Kempinski AM, and Frankenfield CD. Molecular cloning and characterization of the type VII isoform of mammalian adenylyl cyclase expressed widely in mouse tissues and in S49 mouse lymphoma cells. J Biol Chem 269: 28893-28898, 1994[Abstract/Free Full Text].

180.   Wayman, GA, Wei J, Wong S, and Storm DR. Regulation of type I adenylyl cyclase by calmodulin kinase IV in vivo. Mol Cell Biol 16: 6075-6082, 1996[Abstract].

181.   Wei, J, Wayman G, and Storm DR. Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. J Biol Chem 271: 24231-24235, 1996[Abstract/Free Full Text].

182.   Welker, E, Armstrong-James M, Bronchti G, Ourednik W, Gheorghita-Baechler F, Dubois R, Guernsey DL, Van der Loos H, and Neumann PE. Altered sensory processing in the somatosensory cortex of the mouse mutant barrelless. Science 271: 1864-1867, 1996[Abstract].

183.   Whisnant, RE, Gilman AG, and Dessauer CW. Interaction of the two cytosolic domains of mammalian adenylyl cyclase. Proc Natl Acad Sci USA 93: 6621-6625, 1996[Abstract/Free Full Text].

184.   Wu, J, Dent P, Jelinek T, Wolfman A, Weber MJ, and Sturgill TW. Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3',5'-monophosphate. Science 262: 1065-1069, 1993[ISI][Medline].

185.   Wu, Z, Wong ST, and Storm DR. Modification of the calcium and calmodulin sensitivity of the type I adenylyl cyclase by mutagenesis of its calmodulin binding domain. J Biol Chem 268: 23766-23768, 1993[Abstract/Free Full Text].

186.   Wu, ZL, Thomas SA, Villacres EC, Xia Z, Simmons ML, Chavkin C, Palmiter RD, and Storm DR. Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice. Proc Natl Acad Sci USA 92: 220-224, 1995[Abstract].

187.   Xia, Z, Choi E-J, Wang F, Blazynski C, and Storm DR. Type I calmodulin-sensitive adenylyl cyclase is neural specific. J Neurochem 60: 305-311, 1993[ISI][Medline].

188.   Xia, Z, Choi E-J, Wang F, and Storm DR. The type III calcium/calmodulin-sensitive adenylyl cyclase is not specific of olfactory neurons. Neurosci Lett 144: 169-173, 1992[ISI][Medline].

189.   Xia, Z, Refsdal CD, Merchant DM, Dorsa DM, and Storm DE. Distribution of mRNA for the calmodulin-sensitive adenylate cyclase in rat brain: expression in areas associated with learning and memory. Neuron 6: 431-443, 1991[ISI][Medline].

190.   Xia, Z, and Storm DR. Calmodulin-regulated adenylyl cyclases and neuromodulation. Curr Opin Neurobiol 7: 391-396, 1997[ISI][Medline].

191.   Yan, SZ, Hahn D, Huang ZH, and Tang WJ. Two cytoplasmic domains of mammalian adenylyl cyclase form a Gsalpha - and forskolin-activated enzyme in vitro. J Biol Chem 271: 10941-10945, 1996[Abstract/Free Full Text].

192.   Yan, SZ, Huang ZH, Andrews RK, and Tang WJ. Conversion of forskolin-insensitive to forskolin-sensitive (mouse-type IX) adenylyl cyclase. Mol Pharmacol 53: 182-187, 1998[Abstract/Free Full Text].

193.   Yang, B, He B, Abdel-Halim SM, Tibell A, Brendel MD, Bretzel RG, Efendic S, and Hillert J. Molecular cloning of a full-length cDNA for human type 3 adenylyl cyclase and its expression in human islets. Biochem Biophys Res Commun 254: 548-551, 1999[ISI][Medline].

194.   Yoshimura, M, and Cooper DM. Type-specific stimulation of adenylylcyclase by protein kinase C. J Biol Chem 268: 4604-4607, 1993[Abstract/Free Full Text].

195.   Yoshimura, M, and Cooper DMF Cloning and expression of Ca2+-inhibitable adenylyl cyclase from NCB-20 cells. Proc Natl Acad Sci USA 89: 6716-6720, 1992[Abstract].

196.   Yoshimura, M, Ikeda H, and Tabakoff B. µ-Opioid receptors inhibit dopamine-stimulated activity of type V adenylyl cyclase but enhance dopamine-stimulated activity of type VII adenylyl cyclase. Mol Pharmacol 50: 43-51, 1996[Abstract].

197.   Yoshimura, M, and Tabakoff B. Selective effects of ethanol on the generation of cAMP by particular members of the adenylyl cyclase family. Alcohol Clin Exp Res 19: 1435-1440, 1995[ISI][Medline].

198.   Yu, HJ, Unnerstall JR, and Green RD. Determination and cellular localisation of adenylyl cyclase isoenzymes expressed in embryonic chick heart. FEBS Lett 374: 89-94, 1995[ISI][Medline].

199.   Yung, LY, Tsim ST, and Wong YH. Stimulation of cAMP accumulation by the cloned Xenopus melatonin receptor through Gi and Gz proteins. FEBS Lett 372: 99-102, 1995[ISI][Medline].

200.   Zhang, G, Liu Y, Ruoho AE, and Hurley JH. Structure of the adenylyl cyclase catalytic core. Nature 386: 247-253, 1997[ISI][Medline].

201.   Zimmermann, G, and Taussig R. Protein kinase C alters the responsiveness of adenylyl cyclases to G protein alpha  and beta gamma subunits. J Biol Chem 271: 27161-27166, 1996[Abstract/Free Full Text].


Am J Physiol Renal Fluid Electrolyte Physiol 279(3):F400-F416
0363-6127/00 $5.00 Copyright © 2000 the American Physiological Society