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J. Biol. Chem., Vol. 277, Issue 8, 6025-6031, February 22, 2002
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From the Department of Pharmacology, University of Colorado Health
Sciences Center, Denver, Colorado 80262
Ca2+-sensitive adenylyl
cyclases (ACs) depend on capacitative Ca2+ entry (CCE) for
their regulation. Residence of the endogenous Ca2+-inhibitable adenylyl cyclase of C6-2B glioma cells in
cholesterol-enriched caveolae is essential for its regulation by CCE
(Fagan, K. A., Smith, K. E., and Cooper, D. M. F. (2000) J. Biol. Chem. 275, 26530-26537). In the
present study, we established that depletion of cellular cholesterol
ablated the regulation by CCE of a Ca2+-stimulable adenylyl
cyclase, AC8, heterologously expressed in HEK293 cells. We considered
the possibility that a calmodulin-binding domain in the N terminus of
AC8, which is not required for in vitro regulation by
Ca2+, might play a targeting role. Deletion and mutation of
the N terminus did attenuate the enzyme's sensitivity to CCE without altering its in vitro responsiveness to
Ca2+/calmodulin. Both N terminus-deleted AC8 and wild type
AC8 were expressed at the plasma membrane, as shown by imaging analysis of green fluorescence protein-tagged constructs. However, not only wild
type AC8 but also the CCE-insensitive mutants occurred in caveolar
fractions of the plasma membranes, even though a
Ca2+-insensitive adenylyl cyclase, AC7, was excluded from
caveolae. Finally, the AC8 mutants were no more responsive to
nonphysiological elevation of Ca2+ than the wild type. We
conclude that (i) not all adenylyl cyclases reside in caveolae,
(ii) the calmodulin-binding domain in the N terminus of AC8 does not
play a role in caveolar targeting, (iii) the N terminus does play a
role in associating AC8 with factors that confer sensitivity to CCE,
and (iv) residence of Ca2+-sensitive adenylyl cyclases in
caveolae is essential but not sufficient for regulation by CCE.
Residence of Adenylyl Cyclase Type 8 in Caveolae Is Necessary but
Not Sufficient for Regulation by Capacitative Ca2+
Entry*
*
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.
To whom correspondence should be addressed: Dept. of Pharmacology,
Box C-236, University of Colorado Health Sciences Center, 4200 E. Ninth
Ave., Denver, CO 80262. Tel.: 303-315-8964; Fax: 303-315-7097; E-mail:
dermot.cooper@uchsc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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