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J Biol Chem, Vol. 274, Issue 50, 35539-35545, December 10, 1999

Inhibition by Calcium of Mammalian Adenylyl Cyclases*

Jean-Louis GuillouDagger §, Hiroko NakataDagger , and Dermot M. F. Cooper

From the Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262

Ca2+ regulates mammalian adenylyl cyclases in a type-specific manner. Stimulatory regulation is moderately well understood. By contrast, even the concentration range over which Ca2+ inhibits adenylyl cyclases AC5 and AC6 is not unambiguously defined; even less so is the mechanism of inhibition. In the present study, we compared the regulation of Ca2+-stimulable and Ca2+-inhibitable adenylyl cyclases expressed in Sf9 cells with tissues that predominantly express these activities in the mouse brain. Soluble forms of AC5 containing either intact or truncated major cytosolic domains were also examined. All adenylyl cyclases, except AC2 and the soluble forms of AC5, displayed biphasic Ca2+ responses, suggesting the presence of two Ca2+ sites of high (~0.2 µM) and low affinity (~0.1 mM). With a high affinity, Ca2+ (i) stimulated AC1 and cerebellar adenylyl cyclases, (ii) inhibited AC6 and striatal adenylyl cyclase, and (iii) was without effect on AC2. With a low affinity, Ca2+ inhibited all adenylyl cyclases, including AC1, AC2, AC6, and both soluble forms of AC5. The mechanism of both high and low affinity inhibition was revealed to be competition for a stimulatory Mg2+ site(s). A remarkable selectivity for Ca2+ was displayed by the high affinity site, with a Ki value of ~0.2 µM, in the face of a 5000-fold excess of Mg2+. The present results show that high and low affinity inhibition by Ca2+ can be clearly distinguished and that the inhibition occurs type-specifically in discrete adenylyl cyclases. Distinction between these sites is essential, or quite spurious inferences may be drawn on the nature or location of high affinity binding sites in the Ca2+-inhibitable adenylyl cyclases.

* This work was supported by National Institutes of Health Grant GM 32483 (to D. M. F. C.).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. Section 1734 solely to indicate this fact.

Dagger These authors contributed equally to this work.

§ Supported by the Foundation FYSSEN (Paris).

To whom correspondence should be addressed: Dept. of Pharmacology, Campus Box C-236, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262. Tel.: 303-315-89-64; Fax: 303-315-70-97; E-mail: dermot.cooper@uchsc.edu.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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