Elsevier

Cellular Signalling

Volume 11, Issue 9, September 1999, Pages 651-663
Cellular Signalling

Topical review
Functional Properties of Ca2+-Inhibitable Type 5 and Type 6 Adenylyl Cyclases and Role of Ca2+ Increase in the Inhibition of Intracellular cAMP Content

https://doi.org/10.1016/S0898-6568(99)00031-5Get rights and content

Abstract

Among the different adenylyl cyclase (AC) isoforms, type 5 and type 6 constitute a subfamily which has the remarkable property of being inhibited by submicromolar Ca2+ concentrations in addition to Gαi-mediated processes. These independent and cumulative negative regulations are associated to a low basal enzymatic activity which can be strongly activated by Gαs-mediated interactions or forskolin. These properties ensure possible wide changes of cAMP synthesis. Regulation of cAMP synthesis by Ca2+ was studied in cultured or native cells which express naturally type 5 and/or type 6 AC, including well-defined renal epithelial cells. The results underline two characteristics of the inhibition due to agonist-elicited increase of intracellular Ca2+: i) Ca2+ rises achieved through capacitive Ca2+ entry or intracellular Ca2+ release can inhibit AC to a similar extent; and ii) in a same cell type, different agonists inducing similar overall Ca2+ rises elicit a variable inhibition of AC activity. The results suggest that a high efficiency of AC regulation by Ca2+ is linked to a requisite close localization of AC enzyme and Ca2+ rises.

Introduction

Intracellular adenosine 3′:5′-cyclic monophosphate (cAMP) plays a key role in the control of cellular functions. The intracellular content of cAMP results from its synthesis, ensured by the activation of adenylyl cyclases, and from its hydrolysis, catalysed by phosphodiesterases. These two enzyme families comprise multiple isoforms, the regulatory properties of which differ from one isoform to another [1].

Several excellent reviews have previously recalled the general characteristics of adenylyl cyclases and some of the specific properties exhibited by the nine isoforms cloned up to date 1, 2, 3, 4, 5, 6. The regulatory factors include the βγ subunits of the heterotrimeric GTP binding proteins, the activity of protein kinases A and C and/or the intracellular free concentration of Ca2+ ([Ca2+]i) (Table 1). The activity of each adenylyl cyclase (AC) isoform described up to date therefore can integrate signals emerging from the activation of other signalling pathways.

This review focuses on the properties of the AC isoforms type 5 (AC5) and type 6 (AC6) and on the regulation of intracellular cAMP content resulting from their expression in different cell types. The properties of AC5 and AC6 enzymatic activity have been studied in transfected cells or in cells which naturally express these isoforms. Both approaches have allowed to define similar properties which, thus, characterise Ca2+-inhibitable AC. In membrane preparations, one of their fundamental properties is to be inhibited by submicromolar concentrations of Ca2+ in addition to Gαi-mediated processes. In intact cells, the term “Ca2+-inhibitable” AC is particularly appropriate as evidenced by two lines of observations that emerged from several recent studies discussed in this review. First, the magnitude of Ca2+ inhibition is highly variable from one cell type to another and the expression of one Ca2+ inhibitable AC does not always confer a strong inhibition of AC activity by agonists eliciting [Ca2+]i increase. Second, in a given cell type, any [Ca2+]i increase is not able to decrease AC activity. These observations underline a dual specificity of the putative regulation of AC activity by Ca2+, i.e., the cell type involved and the agonist eliciting [Ca2+]i rise.

The first part of this review will recall the properties obtained in AC5- and AC6-transfected cells and their comparison to other AC isoforms. The second part will develop the properties of regulation observed in intact cells which express preferentially, if not exclusively, AC5 and/or AC6 mRNAs and the role of [Ca2+]i increase in the regulation of intracellular cAMP content. Some examples will be taken from defined native cells of the renal tubule which appear particularly suitable to emphasize several properties of Ca2+-inhibitable AC isoforms.

Section snippets

Regulatory properties of type 5 and type 6 adenylyl cyclases

Molecular cloning of type 5 7, 8, 11 and type 6 9, 10, 11, 12, 13 AC has been performed from different cDNA libraries. The intrinsic properties of these isoforms and the factors susceptible to regulate each enzymatic activity have been studied either in intact mammalian cells transfected with the isoform of interest or in membranes prepared from transfected cells or from insect cells infected with recombinant baculovirus. In most experiments, the properties elicited by different AC isoforms

Regulation of intracellular cAMP content and properties of the inhibition elicited by ca2+ in intact cells

The expression of Ca2+ inhibitable AC mRNAs does not always correlate with the functional properties that are observed 56, 57. The properties of regulation linked to the presence of one given mRNA isoform therefore may be difficult to define in some tissues. Different factors can contribute to the difficulty of this analysis, such as the heterogeneity of tissular or cellular preparations, the expression of an unknown AC isoform and/or of several isoforms in a same cell as suggested from the

Conclusion

Type 5 and type 6 adenylyl cyclases exhibit similar enzymatic properties and characteristics of regulation, except the stimulatory effect of PKCs described only with AC5. In cells which express these isoforms, the cAMP content is strongly regulated, either positively by agonist-mediated Gαs activation, or negatively by Gαi-mediated processes and [Ca2+]i increases consecutive to PLC activation or voltage-operated channels. The negative pathways integrate two different and independent mechanisms

Acknowledgements

We thank Professor F. Morel who initiated us to the “kidney world” and to its regulation by adenylyl cyclases. We would like to thank our collaborators who contributed to the studies presented. The authors' own work cited in this review has been supported by grants from the Centre National de la Recherche Scientifique (URA 1290 and 1859) and from the CEA (DBCM, SBCe).

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