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The never-ending pas de deux
Focus on "Capacitative Ca2+ entry is involved in cAMP synthesis in mouse parotid acini"

Françoise Pecker and Jacques Hanoune

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

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FOR WHAT SEEMS LIKE EONS, adenosine 3',5'-cyclic monophosphate (cAMP) and Ca2+ have been competing for supremacy in cellular signaling. They still are.

A study by Watson et al., the current article in focus (Ref. 8, see p. C557 in this issue), brings new insight to the sophisticated control of adenylyl cyclase by Ca2+. The authors show that, in the parotid gland, activation of the enzyme is governed by Ca2+ routed via the capacitative Ca2+ channels.

Contrary to voltage-dependent Ca2+ channels and ligand-gated cation channels, which are expressed only in selected sets of cells (neurons, myocytes, endocrine cells), capacitative Ca2+ entry channels are ubiquitous. These latter channels are activated by stimuli that cause Ca2+ depletion of endoplasmic/sarcoplasmic reticulum stores. Under physiological conditions, their activation is preceded by inositol 1,4,5-trisphosphate (IP3)-induced increases in free intracellular Ca2+ concentration ([Ca2+]i). There is little information as to how or by what mechanisms the capacitative Ca2+ channels are activated: various models have been proposed based on diffusible factors or protein-protein interactions (for reviews see Refs. 1 and 4). The molecular identity of these channels is still questioned; the finding that the transient receptor potential (trp) gene product in Drosophila photoreceptors can function as such a capacitative Ca2+ entry channel may help in the elucidation of the mechanism of capacitative Ca2+ entry (2).

With the use of HEK-293 cells, Fagan et al. (3) have expressed types I and VIII adenylyl cyclases, which, according to in vitro studies, were deemed to be activated by submicromolar Ca2+. It was shown that, in situ, these isoforms of adenylyl cyclase do not sense elevations of cytosolic Ca2+ ([Ca2+]i) due to Ca2+ release from intracellular stores, triggered by either thapsigargin or ionophore. In contrast, the isoforms are stimulated by the capacitative entry of Ca2+ linked to the depletion of internal stores (3). The authors noted that the efficacy of activation of adenylyl cyclase promoted by Ca2+ entry was particularly striking compared with that promoted by Ca2+ release, in light of the higher [Ca2+]i that was achieved by release compared with entry. Fagan et al. concluded that adenylyl cyclase is compartmentalized in specific domains together with the capacitative entry channels and that Ca2+ entering the cell by other means or Ca2+ released in the cytosol does not have access to those domains. It should be pointed out that, in the study by Fagan et al. (3) as well as in the present study by Watson et al. (8), the cAMP increase in response to carbachol is due not only to the capacitative Ca2+ influx but also to Ca2+ released from intracellular stores. Ca2+ release evoked by carbachol occurs through specific IP3 receptors, whereas Ca2+ release evoked by either thapsigargin or ionophore is rather nonspecific and involves Ca2+ entry pathways other than those regulated by IP3 receptors. Taking into account that the parotid cells display a particularly high compartmentation of the internal Ca2+ pool (6), it is tempting to propose that IP3 receptors are also localized in the capacitative Ca2+ influx/adenylyl cyclase domains. Such a compartmentation is reminiscent of the cAMP compartmentation produced on beta -agonist stimulation reported in myocytes (5). This stimulation causes a local activation of L-type channels, leading in turn to inhibition of the neighboring types V and VI adenylyl cyclases (9).

Overall, the study by Watson et al. (8) provides a direct demonstration that capacitative Ca2+ influx can increase cellular cAMP in native cells. However, a specific aspect of this study should be noted: the Ca2+-promoted increase in cAMP is observed only in conditions in which cellular cAMP is already elevated, i.e., in the presence of isoproterenol or in the presence of phosphodiesterase inhibitors. This is similar to the conditions in which activation by Ca2+ of type III adenylyl cyclase is observed: in contrast with the activation of types I and VIII, activation of adenylyl cyclase type III by Ca2+ occurs only when the enzyme is stimulated by other factors (e.g., forskolin, isoproterenol). Watson et al. (8) propose that capacitative Ca2+ entry augments cAMP via the activation of type VIII adenylyl cyclase, since this isoform is expressed in parotid acini. However, the possible participation of other isoforms cannot be eliminated at this point. Furthermore, the fact that Sakai and Ambudkar (7) have shown that, in parotid acini, regulation of Ca2+ influx by Ca2+ store depletion involves phosphorylation-dephosphorylation mechanisms might explain the differences in Ca2+ influx responses observed in basal and activated conditions.

If compartmentation of the signaling pathways is to be the final conclusion of the Ca2+-cAMP interplay, this is perhaps not unexpected, especially given the increasing recognition of subcellular organization of signaling pathways. However, unequivocal evidence for such organization of Ca2+ entry channels and adenylyl cyclase isoforms has yet to be demonstrated.

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1.   Berridge, M. J. Capacitative calcium entry. Biochem. J. 312: 1-11, 1995[Medline].

2.   Birnbaumer, L., X. Zhu, M. Jiang, G. Boulay, M. Peyton, B. Vannier, D. Brown, D. Platano, H. Sadeghi, E. Stefani, and M. Birnbaumer. On the molecular basis and regulation of cellular capacitative calcium entry: roles for Trp proteins. Proc. Natl. Acad. Sci. USA 93: 15195-15202, 1996[Abstract/Free Full Text].

3.   Fagan, K. A., R. Mahey, and D. M. F. Cooper. Functional co-localization of transfected Ca2+-stimulable adenylyl cyclases with capacitative Ca2+ entry sites. J. Biol. Chem. 271: 12438-12444, 1996[Abstract/Free Full Text].

4.   Fasolato, C., B. Innocenti, and T. Pozzan. Receptor-activated Ca2+ influx: how many mechanisms for how many channels? Trends Pharmacol. Sci. 15: 77-83, 1994[Medline].

5.   Jurevicius, J., and R. Fischmeister. cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta -adrenergic agonists. Proc. Natl. Acad. Sci. USA 93: 295-299, 1996[Abstract/Free Full Text].

6.   Lee, M. G., X. Xu, W. Zeng, J. Diaz, R. J. H. Wojcikiewicz, T. H. Kuo, F. Wuytack, L. Racymaekers, and S. Muallem. Polarized expression of Ca2+ channels in pancreatic and salivary gland cells. J. Biol. Chem. 272: 15765-15770, 1997[Abstract/Free Full Text].

7.   Sakai, T., and I. S. Ambudkar. Role for protein phosphatase in the regulation of Ca2+ influx in parotid gland acinar cells. Am. J. Physiol. 271 (Cell Physiol. 40): C284-C294, 1996[Abstract/Free Full Text].

8.   Watson, E. L., Z. Wu, K. L. Jacobson, D. R. Storm, J. C. Singh, and S. M. Ott. Capacitative Ca2+ entry is involved in cAMP synthesis in mouse parotid acini. Am. J. Physiol. 274 (Cell Physiol. 43): C557-C565, 1998[Abstract/Free Full Text].

9.   Yu, H. J., H. Ma, and R. D. Green. Calcium entry via L-type calcium channels acts as a negative regulator of adenylyl cyclase activity and cyclic AMP levels in cardiac myocytes. Mol. Pharmacol. 44: 689-693, 1993[Abstract].


AJP Cell Physiol 274(3):C555-C556
0363-6143/98 $5.00 Copyright © 1998 the American Physiological Society




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