From the Department of Biochemistry, Molecular
Biology, and Biophysics, University of Minnesota, St. Paul,
Minnesota 55108 and the Molecular Biology and Virology Laboratory, The
Salk Institute for Biological Studies,
San Diego, California 92186
In 1956, two seemingly disparate but profoundly
prophetic papers were published. Kisch (1) observed that atrial, but
not ventricular, cardiac cells contain a highly developed Golgi
network, reminiscent of a secretory system, and Henry and colleagues
(2) discovered that elevated left atrial pressure stimulates urine output. Twenty-five years later the connection between these studies and the heart and the kidney was made when de Bold and colleagues (3)
determined that rat atrial extracts contain a potent diuretic and
natriuretic factor. Since the publication of this landmark paper in
1981, three structurally related but genetically distinct peptides with
vasodilatory properties, called atrial natriuretic factor, also known
as atrial natriuretic peptide
(ANP),1 brain natriuretic
peptide (BNP), and C-type natriuretic peptide (CNP) have been purified
and molecularly cloned (4, 5) (Fig. 1).
INTRODUCTION
TOP
INTRODUCTION
Receptor Structure, Topology,...
Glycosylation
Phosphorylation
Receptor Activation
Homologous Desensitization
Heterologous Desensitization
Future Directions
REFERENCES
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Fig. 1.
Model of the structures and functions of
natriuretic peptides and their receptors. See text for
description. Numbering is for rat sequences. Drawings are not to
scale.
The primary signaling molecules for these hormones are natriuretic
peptide receptor-A (NPR-A) and natriuretic peptide receptor-B (NPR-B)
(Fig. 1). They are members of the cell-surface family of guanylyl
cyclase receptors, enzymes that catalyze the synthesis of the
intracellular second messenger, cGMP (5, 6). Hence, they are sometimes
referred to as guanylyl cyclase-A and guanylyl cyclase-B or GC-A and
GC-B. NPR-A is activated by physiologic concentrations of ANP and BNP,
but not CNP (7, 8). Conversely CNP, but not ANP or BNP, activates NPR-B
(7, 8). In addition, all three natriuretic peptides bind the
natriuretic peptide clearance receptor (NPR-C). In many tissues, NPR-C
is the most abundant of the three natriuretic peptide receptors, and it
binds ANP, BNP, and CNP with relatively similar affinities (9). It has only 37 intracellular amino acids and does not possess guanylyl cyclase
activity. It is thought to primarily control the local concentrations
of natriuretic peptides that are available to bind NPR-A and NPR-B (9),
but a signaling function for this receptor has also been reported (10).
In this review, we summarize the available data on the structure
and regulation of NPR-A and NPR-B.
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Receptor Structure, Topology, and Oligomeric State |
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The basic topology of NPR-A and -B consists of an ~450-amino acid extracellular ligand-binding domain, a 21-residue hydrophobic membrane-spanning region, and a 566- or 568-amino acid intracellular domain, respectively (Fig. 1). The latter can be further divided into a juxtamembrane region of ~250 amino acids that is similar to known protein kinases called the kinase homology domain (KHD), a 41-amino acid amphipathic coiled-coil hinge region, and a roughly 250-amino acid C-terminal guanylyl cyclase catalytic domain. In the absence of ligand, NPR-A exists as a homodimer or homotetramer, and ANP binding does not lead to further aggregation (11-13). Multiple domains that are located both outside and inside the plasma membrane mediate the oligomerization of NPR-A. The intracellular dimerization interface region has been mapped to the amphipathic sequence that bisects the KHD and cyclase domains (14). The deletion of this region results in monomeric and inactive intracellular constructs, suggesting that dimerization of the cyclase domains is required for catalytic activity. NPR-B is also an oligomer in the absence of ligand (15).
The disulfide bonding structure of an extracellular secreted version of rat NPR-A has been determined (16). In this receptor, intramolecular bonds were found between Cys-60 and Cys-86, Cys-164 and Cys-215, and Cys-423 and Cys-432. Hence, the NPR-A extracellular domain contains three intramolecular but no intermolecular disulfide bonds. Two groups have addressed the role of the juxtamembrane cysteines in NPR-A. Labrecque et al. (17) found that the conversion of Cys-423 to serine resulted in a receptor variant that migrated at twice the molecular weight of the wild-type receptor under nonreducing but not reducing SDS-polyacrylamide gel electrophoresis conditions. They concluded that the removal of Cys-423 allowed Cys-432 to form an intermolecular disulfide bond with the corresponding residue on a separate polypeptide chain. This mutant's basal activity is elevated 20-40-fold compared with the wild-type receptor but has a diminished ability to be activated by ANP and/or ATP. In separate experiments, Huo and colleagues (18) found that the mutation of both Cys-423 and Cys-432 to serine results in a variant with similar guanylyl cyclase properties as the single Cys-423 mutant. Together, these data emphasize the importance of the juxtamembrane intrachain disulfide bond in NPR-A activation and suggest the increased basal activity observed with the Cys-423 mutant results from the loss of an intramolecular disulfide bond, not from the creation of an intermolecular disulfide bond. Studies of the disulfide binding pattern of NPR-B have not been reported, but because the cysteines involved in the N-terminal (Cys-53 and Cys-79) and juxtamembrane disulfide bonds (Cys-417 and Cys-426) are conserved between NPR-A and NPR-B, it is likely that these bonds form in NPR-B as well. A middle disulfide bond might be formed between Cys-205 and Cys-314 because these are the only remaining Cys residues in the extracellular domain of this receptor.
The crystal structure of the glycosylated, unliganded, dimerized
hormone-binding domain of NPR-A has been solved at 2.0-Å resolution
(19). The monomer consists of two interconnected subdomains, each
encompassing a central -sheet flanked by
-helices, and exhibits a
type I periplasmic binding protein fold. Dimerization appears to be
mediated by juxtaposition of 2 × 2 parallel helices that bring
the two protruding C termini in close proximity. Affinity-labeling experiments indicated that residues 4 and 18 of ANP bind in the vicinity of Met-173 of NPR-A and that the C terminus of ANP binds near
His-195. The assignment of receptor contact residues by the crystallography group is consistent with a previous report
demonstrating that the amino portion of ANP could be cross-linked to
the NPR-A chymotryptic peptide Met-173 to Phe-188 (20). The structure of an ANP-NPR-A complex has not been solved, but van den Akker et
al. (19) speculate that the dimeric receptor contains two spatially separated ANP-binding sites, which yields a ligand-receptor stoichiometry of 2:2. This is consistent with previous studies that
indicated the stoichiometry of binding is 1:1 (21, 22) or 2:2 (23) but
not with a study that suggested a stoichiometry of 1:2 (24). Perhaps
the most surprising finding to come from the initial structural work on
NPR-A is the presence of an apparent chloride-binding site buried
within the N-terminal portion of each monomer. Surprisingly, Misono
(25) reported that chloride is absolutely required for ANP binding to
the extracellular domain of NPR-A. Whether chloride is required for
hormone binding to the full-length receptor or to NPR-B or NPR-C
remains to be determined. In addition, whether chloride binding is
reversible and therefore regulatory also remains to be answered.
However, because the chloride concentration that is necessary for 50%
of the maximal ANP binding response (EC50 = 0.6 mM) is 2 orders of magnitude below physiologic concentrations, this appears unlikely.
Presently, no direct data are available on the crystal structure of any
guanylyl cyclase catalytic domain. However, because of the high
sequence similarity between the catalytic domains of adenylyl and
guanylyl cyclases, the latter have been molecularly modeled based on
the coordinates from the former (26). Both cyclase domains appear to
form a wreathlike structure with the mammalian adenylyl cyclases and
soluble guanylyl cyclases containing one active site per heterodimer
and the membrane guanylyl cyclases, including NPR-A and NPR-B,
containing two active sites per homodimer (27). Because the residues
that interact with ribose, triphosphate, and Mg2+ in
adenylyl cyclase are conserved in guanylyl cyclases, it is believed
they serve similar functions in both enzymes. Hence, the residues that
interact with the purine base determine substrate specificity. In the
model of the nucleotide-binding site of the retinal guanylyl cyclase
(ret-GC-1 or GC-E), Glu-925 and Cys-997 are essential for nucleotide
discrimination and are envisioned to form critical hydrogen bonds with
the N-1, N-2, and O-6 atoms of guanine, respectively (26). This model
has now been tested and confirmed by Tucker and colleagues (28), who
changed the substrate specificity of retinal guanylyl cyclase-1 from
guanine to adenine by mutating Glu-925 and Cys-997 to Lys and Asp, the corresponding residues in adenylyl cyclases. These residues are conserved in NPR-A and NPR-B and are likely to serve similar functions in their active sites as well.
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Glycosylation |
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NPR-A purified from transfected 35S-labeled 293 cells
displays considerable size heterogeneity (13). The explanation for this variability is incomplete N-linked glycosylation because
N-glycosidase treatment collapses all the higher molecular
weight forms to a single species of ~116 kDa, the expected molecular
mass of the core polypeptide (13). Direct sequencing of the N termini
of human NPR-IgG fusion proteins purified from Chinese hamster ovary cells indicated that Asn-2 and Asn-13 of NPR-A and Asn-2 of NPR-B are
glycosylated (29). In Cos-1 cells, an extracellular truncation mutant
of rat NPR-A was found to be glycosylated at positions Asn-13, Asn-180,
Asn-306, Asn-347, and Asn-395 (30). Asn-2 is not conserved in the rat
version of NPR-A. Enzymatic deglycosylation of the extracellular domain
of NPR-A does not significantly affect its ANP binding properties (30).
In contrast, Fenrick and colleagues (31) determined that only the fully
glycosylated form of NPR-B could be cross-linked to
125I-CNP. Furthermore, cotransfection with truncated
versions of NPR-B or unrelated receptors that decreased the amount of
the fully glycosylated form of NPR-B, presumably by saturating the cellular glycosylation machinery, reduced its ability to produce cGMP
in response to CNP (31). Mutational analysis of the asparagines present
in the extracellular domain of bovine NPR-B suggested that five of the
seven total sites are glycosylated, and the mutation of Asn-2 reduced
CNP binding by 90%, presumably because of improper receptor folding
(32). Collectively, these results suggest that glycosylation is
required for proper receptor folding or targeting, but not for NP binding.
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Phosphorylation |
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The first direct indication that NP receptors are regulated by
protein phosphorylation came in 1992 when NPR-A purified from metabolically labeled HEK 293 cells was shown to contain
32P (33, 34). The stoichiometry of phosphate to receptor
molecules was not determined, but the fact that dephosphorylation
resulted in a slight electrophoretic mobility shift indicated that it
is at least 1:1 (33). Despite the homology of the NPR-A KHD to the
tyrosine kinase domain of the platelet-derived growth factor receptor, phosphoamino acid analysis detected only phosphoserine and
phosphothreonine (33-35). When whole cells or membrane preparations containing the NPR-A were incubated with ANP or the purified catalytic subunit of protein phosphatase 2A, respectively, the receptor was
dephosphorylated in parallel with losses in ANP-dependent guanylyl cyclase activity (33). NPR-A isolated from resting 293 cells
is phosphorylated on six residues (Ser-497, Thr-500, Ser-502, Ser-506,
Ser-510, Thr-513) located within the glycine-rich elbow and putative
ATP-binding region of its KHD (36). Replacement of any of these
phosphorylated amino acids, but not residues flanking this region, with
alanine results in decreased ANP-dependent guanylyl cyclase
activities (36). Receptors lacking four or more of these sites are
completely unresponsive to hormone. NPR-B is also regulated by
phosphorylation (37) and has five known phosphorylation sites within
the N-terminal portion of its KHD (Thr-513, Thr-516, Ser-518, Ser-523,
Ser-526) (38). These data indicate that receptor phosphorylation is not
merely modulatory but is absolutely required for NP signal transduction. The NP receptor kinase has not been identified.
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Receptor Activation |
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As a starting point for the molecular analysis of
NP-dependent activation and desensitization of NPR-A, we
have constructed a working model of this process (Fig.
2). In the absence of NP, the receptor
exists as a homodimer or homotetramer. It is highly phosphorylated, and
its guanylyl cyclase activity is tightly repressed. Upon NP binding,
the oligomeric state of the receptor does not change (12, 39), which
indicates that receptor activation is not simply the result of
ligand-dependent receptor oligomerization as is the case
for many growth factor receptors. On the other hand, ANP binding does
cause the extracellular juxtamembrane region of NPR-A to become
susceptible to protease cleavage (18), which suggests that hormone
binding induces a conformational change in this proline-rich
"hinge" portion of the receptor. Exactly how hormone binding
transmits an activation signal across the membrane is unclear. However,
because ATP is required for maximal NP-dependent activation
and receptors lacking the KHD are constitutively active in the absence
of ANP (40), one possibility is that hormone binding facilitates ATP
binding to the KHD. Once ATP is bound, a conformational change occurs
within the KHD that facilitates three subsequent events. First, the
normal inhibitory effect that the KHD has on catalytic activity is
relieved and the guanylyl cyclase domains are allowed to come together
to form two active sites per dimer. Second, an increased dissociation
rate decreases the affinity of the extracellular domain of NPR-A for
ANP. This effect also requires the KHD and is observed in whole cells
as a time-dependent shift from high to low affinity ANP
binding (41). Third, the conformational change in the KHD may expose
the phosphorylated residues to a constitutively active, or perhaps a
cGMP-activable, protein phosphatase. In addition, the ATP-bound KHD may
be a poorer substrate for the NPR-A kinase. The resulting
dephosphorylated receptor is unresponsive to further hormonal
stimulation.
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In contrast to ATP, the diuretic drug amiloride stabilizes the high
affinity binding state and inhibits the hormone-dependent cyclase activity of NPR-A (41, 42). Because high concentrations of
amiloride inhibit the ATP-dependent activation of NPR-A, it has been suggested that ATP and amiloride compete for the same site
(41). However, amiloride, but not the ATP, modulated the affinity of
NPR-A for ANP in preparations that were subjected to limited trypsin
proteolysis, suggesting that amiloride and ATP bind to different sites
(24). The location of the ATP-binding site has not been determined, but
it may reside within the NPR-A polypeptide because ATP analogs modestly
activate guanylyl cyclase (43) and inhibit NP binding activities (44)
of highly purified receptor preparations. The
503GXGXXXG509 sequence
within the KHD has been suggested to be the location of ATP interaction
because of its similarity to the consensus ATP binding motif
(GXGXXG) found in many protein kinases. In fact, this region has been dubbed the ATP regulatory domain or "ARM" by
some investigators to emphasize its putative regulatory role (45).
However, no direct ATP binding or cross-linking studies have been
presented to support this hypothesis. These negative results are not
unexpected because the EC50 for ATP activation of NPR-A in
guanylyl cyclase assays is ~0.1 mM (46). Hence, if this
EC50 is reflective of its binding constant for NPR-A, ATP
may not bind tightly enough to obtain positive binding or cross-linking
data. Regardless, this glycine motif is not required for ATP binding
because the conversion of all three glycines to alanine has little or
no effect on the activation of NPR-A (34). Other mutations within this
region do decrease hormone-dependent activity, but they
likely result from reductions in the phosphorylation state of the
receptor (38).
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Homologous Desensitization |
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Because synthetic BNP (Nesiritide) has proven to be clinically beneficial in the treatment of congestive heart failure (47), an understanding of the mechanisms involved in the desensitization of these receptors is important from a basic science and a clinical perspective. Hormone-dependent activities of NPR-A and NPR-B can be reduced by chronic exposure to NPs, known as homologous desensitization, or by exposure to agents other than NPs, referred to as heterologous desensitization. Homologous desensitization can be divided into processes that are or are not mediated by receptor degradation, such as down-regulation and dephosphorylation, respectively. Mechanistic analysis of the homologous desensitization of NPR-A and NPR-B has been hampered by the fact that these receptors are often found in cells that also express NPR-C. Hence, losses in NP binding could theoretically result from the down-regulation of the cyclase-linked receptors, NPR-C, or both. In addition, because of the high affinity of these receptors for ligands, prebound NP can mask their ability to bind subsequent NP, a process known as prior receptor occupation (48). This phenomenon can lead to an underestimate of the amount of receptor present in cells and the erroneous conclusion that they are degraded when, in fact, their binding sites are masked.
One study that attempted to circumvent these potential pitfalls employed human embryonic kidney 293 cells that stably express NPR-A but have no detectable NPR-B or NPR-C (33). Metabolic labeling of these cells with [32P]orthophosphate indicated that NPR-A is highly phosphorylated in the absence of NPs and that ligand exposure results in a time-dependent dephosphorylation and desensitization of the receptor. The phosphorylation state of the receptor was tightly correlated with its hormone-dependent guanylyl cyclase activity. The decreased 32P signal was not explained by protein degradation because ANP exposure did not significantly reduce the amount of NPR-A purified from cells that were labeled with [35S]Met/Cys. In a separate study, tryptic phosphopeptide maps of overexpressed NPR-A from NIH-3T3 cells indicated that ANP exposure did not stimulate the dephosphorylation of a specific phosphopeptide, although it clearly resulted in the dephosphorylation of the receptor (35). A similar scenario was reported for NPR-B (37). One explanation for these observations is that cells exposed to NP contain two pools of receptors, one that is maximally phosphorylated and another that is completely dephosphorylated. Another possibility is that all phosphorylation sites are dephosphorylated to an equal extent in hormone-exposed cells.
Homologous desensitization of NPR-A has been observed in
vitro as well. Foster and Garbers (49) demonstrated that ATPS but not the nonhydrolyzable ATP analog, AMPPNP, could sensitize NPR-A
to subsequent stimulation by ANP and AMPPNP in crude membranes, an
effect that presumably results from the limited ability of protein
phosphatases to dephosphorylate thiophosphorylated substrates. They
also found that the serine/threonine protein phosphatase inhibitor,
microcystin, could prolong the maintenance of the initial rate of the
reaction and increase the total amount of cGMP formed in guanylyl
cyclase assays, again suggesting that dephosphorylation was sufficient
for desensitization. To determine whether NPR-A was the target of the
phosphatase, all six phosphorylation sites were mutated to glutamate to
mimic a constitutively phosphorylated form of NPR-A (NPR-A-6E) (50).
This receptor, but not one containing analogous alanine mutations, is
stimulated 10-fold by ANP and ATP. In contrast to the wild-type
receptor, NPR-A-6E is activated equally well by ATP and AMPPNP and is
completely unaffected by microcystin. These data suggest that the
superior ability of ATP
S and ATP to activate NPR-A results from
their ability to serve as substrates in a protein kinase reaction and
that the protein that is being dephosphorylated in the in
vitro cyclase assay is the receptor itself. Furthermore, NPR-A-6E,
which cannot shed its negative charge via dephosphorylation, was shown
to be resistant to homologous desensitization (50). These results
indicate that NPR-A and NPR-B are homologously desensitized by receptor
dephosphorylation, a unique paradigm compared with most
G-protein-coupled receptors that are desensitized by direct phosphorylation.
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Heterologous Desensitization |
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The vasoconstrictory hormones arginine-vasopressin, angiotensin
II, and endothelin, which activate protein kinase C (PKC) through the
stimulation of phospholipase C, antagonize the actions
of natriuretic peptides and decrease both ANP- and
CNP-dependent cGMP elevations in cultured cell lines
(51-53). The reduced cGMP concentrations result from a
calcium-dependent increase in phosphodiesterase activity
(52, 54) and a PKC-dependent decrease in guanylyl cyclase
activity (35, 52, 55). Activation of PKC appears to be necessary and
sufficient for the latter effect because phorbol 12-myristate
13-acetate (PMA), a direct activator of PKC, mimics and inhibitors of
PKC block the ability of these hormones to desensitize natriuretic
peptide receptors (35, 52, 55). The antagonism between these systems
exists in the absence of strong PKC activators as well because the
down-regulation of PKC by chronic exposure to PMA (56) or angiotensin
II (48) results in the sensitization of NPR-A to ANP. Hence, the
activities of NPR-A and NPR-B are under the constant surveillance of
the renin-angiotensin as well as other PKC-activating systems.
Studies involving in vitro phosphorylation of NPR-A in
crude membranes suggested that PKC directly phosphorylates NPR-A (57). However, interpretation of these observations is complicated by subsequent studies employing specific antibodies in which activation of
PKC in whole cells resulted in the dephosphorylation, not
phosphorylation, of NPR-A (35). Unlike the global dephosphorylation
associated with the homologous process, the heterologous
desensitization is associated with the dephosphorylation of a single
site or small subset of the total. Currently the identity of this
site(s) within NPR-A is not known. PMA exposure results in the
selective dephosphorylation of Ser-523 in NPR-B and reduces both basal
and hormone-dependent cyclase activities (58). Importantly,
replacement of this amino acid with alanine or glutamate abolished the
inhibition, indicating that dephosphorylation of this single serine
residue accounts for heterologous desensitization of NPR-B. Consistent
with these data are results of Chrisman and Garbers (59) showing that
platelet-derived growth factor treatment of mouse fibroblasts results
in the dephosphorylation and desensitization of NPR-B. Because this
growth factor signals, in part, by activating PKC via phospholipase
C, dephosphorylation of Ser-523 may be instrumental in this process
as well. Whether the PKC-dependent dephosphorylation of
NPR-A and NPR-B results from the activation of a protein phosphatase or
the inhibition of a protein kinase is not known nor is the identity of
the responsible protein kinase or phosphatase.
Finally, although both homologous desensitization and heterologous
desensitization are mediated by dephosphorylation, several observations
suggest that each pathway is unique. First, homologous but not
heterologous desensitization requires NP binding. Second, heterologous
but not homologous desensitization requires PKC (35, 55). Third,
homologous desensitization involves global receptor dephosphorylation,
whereas the heterologous process results in the loss of single
phosphate (35). Last, the combined effect of ANP and PMA is greater
than either alone, indicating that these processes are additive (35,
55). Whether each process involves the same or a different protein
kinase and phosphatase remains to be determined.
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Future Directions |
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Over the past 15 years much has been learned about the location,
structure, and physiologic function of NPR-A and NPR-B (4-6). Within
the next few years it is likely that molecules will be discovered that
regulate these NP receptors. Clearly the NP receptor kinase and
phosphatase are prime candidates for identification. Because
phosphorylation is obligatory for the activation of NPR-A and NPR-B,
loss of function mutations within the enzyme(s) that mediates this
process may yield phenotypes similar to those of animals lacking NPs.
Hence, it is possible that some forms of idiopathic hypertension or
dwarfism may be explained by mutations in the NP receptor kinase.
Likewise, activating mutations within the NP receptor phosphatase may
result in these diseases. The identification of proteins that regulate
NPR-A and NPR-B may provide additional drug targets for the treatment
of these and other diseases.
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ACKNOWLEDGEMENTS |
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We are grateful to the many people who communicated results prior to publication and apologize to those whose work we were unable to reference because of space limitations. We thank Sarah Abbey and Jamie Simon for help with the figures.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001.
§ To whom correspondence should be addressed: Dept. of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 356 Gortner Laboratory, 1479 Gortner Ave., St. Paul, MN 55108. Tel.: 612-624-7251; Fax: 612-624-7282; E-mail: Potter@tc.umn.edu.
Published, JBC Papers in Press, January 10, 2001, DOI 10.1074/jbc.R000033200
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ABBREVIATIONS |
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The abbreviations used are:
ANP, atrial
natriuretic peptide;
BNP, brain natriuretic peptide;
CNP, C-type
natriuretic peptide;
HEK, human embryonic kidney;
KHD, kinase homology
domain;
NP, natriuretic peptide;
NPR-A, natriuretic peptide receptor A;
NPR-B, natriuretic peptide receptor B;
GC, guanylyl cyclase;
ATPS, adenosine 5'-O-(thiotriphosphate);
AMPPNP, adenosine
5'-(
,
-imino)triphosphate;
PKC, protein kinase C;
PMA, phorbol 12-myristate 13-acetate.
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