This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Toya, Y. Articles by Ishikawa, Y. Search for Related Content PubMed PubMed Citation Articles by Toya, Y. Articles by Ishikawa, Y.

Inhibition of Adenylyl Cyclase by Caveolin Peptides¹

Cardiovascular and Pulmonary Research Institute (Y.T., C.S., Y.I.), Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212; and Department of Molecular Pharmacology (J.C., M.P.L.), Albert Einstein Medical College, New York, New York 10461

Address all correspondence and requests for reprints to: Yoshihiro Ishikawa, M.D., Ph.D., Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212. E-mail: yishikaw{at}pgh.auhs.edu

Caveolae and their principal component caveolin have been implicated in playing a major role in G protein-mediated transmembrane signaling. We examined whether caveolin interacts with adenylyl cyclase, an effector of G protein signaling, using a 20-mer peptide derived from the N-terminus scaffolding domain of caveolin-1. When tissue adenylyl cyclases were examined, cardiac adenylyl cyclase was inhibited more potently than other tissue adenylyl cyclases. The caveolin-1 peptide inhibited type V, as well as type III adenylyl cyclase, overexpressed in insect cells, whereas the same peptide had no effect on type II. The caveolin-3 scaffolding domain peptide similarly inhibited type V adenylyl cyclase. In contrast, peptides derived from the caveolin-2 scaffolding domain and a caveolin-1 nonscaffolding domain had no effect. Kinetic studies showed that the caveolin-1 peptide decreased the maximal rate (V_max) value of type V without changing the Michaelis constant (Km) value for the substrate ATP. Studies with various truncations and point mutations of this peptide revealed that a minimum of 16 amino acid residues and intact aromatic residues are important for the inhibitory effect. The potency of inhibition was greater when adenylyl cyclase was in stimulated condition vs. basal condition. Thus, caveolin may be another cellular component that regulates adenylyl cyclase catalytic activity. Our results also suggest that the caveolin peptide may be used as an isoform-selective inhibitor of adenylyl cyclase.

This article has been cited by other articles:

				M. Pagano, M. A. Clynes, N. Masada, A. Ciruela, L.-J. Ayling, S. Wachten, and D. M. F. Cooper Insights into the residence in lipid rafts of adenylyl cyclase AC8 and its regulation by capacitative calcium entry Am J Physiol Cell Physiol, March 1, 2009; 296(3): C607 - C619. [Abstract] [Full Text] [PDF]

				A. S. Augustus, J. Buchanan, S. Addya, G. Rengo, R. G. Pestell, P. Fortina, W. J. Koch, A. Bensadoun, E. D. Abel, and M. P. Lisanti Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H657 - H666. [Abstract] [Full Text] [PDF]

				A. J. Halayko, T. Tran, and R. Gosens Phenotype and Functional Plasticity of Airway Smooth Muscle: Role of Caveolae and Caveolins Proceedings of the ATS, January 1, 2008; 5(1): 80 - 88. [Abstract] [Full Text] [PDF]

				D. Willoughby and D. M. F. Cooper Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains Physiol Rev, July 1, 2007; 87(3): 965 - 1010. [Abstract] [Full Text] [PDF]

				A. F. El-Yazbi, W. J. Cho, R. Schulz, and E. E. Daniel Caveolin-1 knockout alters beta-adrenoceptors function in mouse small intestine Am J Physiol Gastrointest Liver Physiol, December 1, 2006; 291(6): G1020 - G1030. [Abstract] [Full Text] [PDF]

				W. E. Schutzer, J. F. Reed, and S. L. Mader Decline in caveolin-1 expression and scaffolding of G protein receptor kinase-2 with age in Fischer 344 aortic vascular smooth muscle Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2457 - H2464. [Abstract] [Full Text] [PDF]

				X.-L. Wang, D. Ye, T. E. Peterson, S. Cao, V. H. Shah, Z. S. Katusic, G. C. Sieck, and H.-C. Lee Caveolae Targeting and Regulation of Large Conductance Ca2+-activated K+ Channels in Vascular Endothelial Cells J. Biol. Chem., March 25, 2005; 280(12): 11656 - 11664. [Abstract] [Full Text] [PDF]

				F. Capozza, A. W. Cohen, M. W.-C. Cheung, F. Sotgia, W. Schubert, M. Battista, H. Lee, P. G. Frank, and M. P. Lisanti Muscle-specific interaction of caveolin isoforms: differential complex formation between caveolins in fibroblastic vs. muscle cells Am J Physiol Cell Physiol, March 1, 2005; 288(3): C677 - C691. [Abstract] [Full Text] [PDF]

				A. J. Crossthwaite, T. Seebacher, N. Masada, A. Ciruela, K. Dufraux, J. E. Schultz, and D. M. F. Cooper The Cytosolic Domains of Ca2+-sensitive Adenylyl Cyclases Dictate Their Targeting to Plasma Membrane Lipid Rafts J. Biol. Chem., February 25, 2005; 280(8): 6380 - 6391. [Abstract] [Full Text] [PDF]

				A. Sobolewski, K. B. Jourdan, P. D. Upton, L. Long, and N. W. Morrell Mechanism of cicaprost-induced desensitization in rat pulmonary artery smooth muscle cells involves a PKA-mediated inhibition of adenylyl cyclase Am J Physiol Lung Cell Mol Physiol, August 1, 2004; 287(2): L352 - L359. [Abstract] [Full Text] [PDF]

				V. O. Rybin, P. W. Grabham, H. Elouardighi, and S. F. Steinberg Caveolae-associated proteins in cardiomyocytes: caveolin-2 expression and interactions with caveolin-3 Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H325 - H332. [Abstract] [Full Text] [PDF]

				P. Gargalovic and L. Dory Caveolins and macrophage lipid metabolism J. Lipid Res., January 1, 2003; 44(1): 11 - 21. [Abstract] [Full Text] [PDF]

				K. E. Smith, C. Gu, K. A. Fagan, B. Hu, and D. M. F. Cooper Residence of Adenylyl Cyclase Type 8 in Caveolae Is Necessary but Not Sufficient for Regulation by Capacitative Ca2+ Entry J. Biol. Chem., February 15, 2002; 277(8): 6025 - 6031. [Abstract] [Full Text] [PDF]

				K. Scholich, S. Pierre, and T. B. Patel Protein Associated with Myc (PAM) Is a Potent Inhibitor of Adenylyl Cyclases J. Biol. Chem., December 7, 2001; 276(50): 47583 - 47589. [Abstract] [Full Text] [PDF]

				B. Razani and M. P. Lisanti Two distinct caveolin-1 domains mediate the functional interaction of caveolin-1 with protein kinase A Am J Physiol Cell Physiol, October 1, 2001; 281(4): C1241 - C1250. [Abstract] [Full Text] [PDF]

				T. Fujita, Y. Toya, K. Iwatsubo, T. Onda, K. Kimura, S. Umemura, and Y. Ishikawa Accumulation of molecules involved in {alpha}1-adrenergic signal within caveolae: caveolin expression and the development of cardiac hypertrophy Cardiovasc Res, September 1, 2001; 51(4): 709 - 716. [Abstract] [Full Text] [PDF]

				R. S. Ostrom, S. R. Post, and P. A. Insel Stoichiometry and Compartmentation in G Protein-Coupled Receptor Signaling: Implications for Therapeutic Interventions Involving Gs J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 407 - 412. [Abstract] [Full Text]

				R. D. Lasley, P. Narayan, A. Uittenbogaard, and E. J. Smart Activated Cardiac Adenosine A1 Receptors Translocate Out of Caveolae J. Biol. Chem., February 11, 2000; 275(6): 4417 - 4421. [Abstract] [Full Text] [PDF]

				J. A. Engelman, X. L. Zhang, B. Razani, R. G. Pestell, and M. P. Lisanti p42/44 MAP Kinase-dependent and -independent Signaling Pathways Regulate Caveolin-1 Gene Expression. ACTIVATION OF RAS-MAP KINASE AND PROTEIN KINASE A SIGNALING CASCADES TRANSCRIPTIONALLY DOWN-REGULATES CAVEOLIN-1 PROMOTER ACTIVITY J. Biol. Chem., November 5, 1999; 274(45): 32333 - 32341. [Abstract] [Full Text] [PDF]

				E. J. Smart, G. A. Graf, M. A. McNiven, W. C. Sessa, J. A. Engelman, P. E. Scherer, T. Okamoto, and M. P. Lisanti Caveolins, Liquid-Ordered Domains, and Signal Transduction Mol. Cell. Biol., November 1, 1999; 19(11): 7289 - 7304. [Full Text] [PDF]

				B. Razani, C. S. Rubin, and M. P. Lisanti Regulation of cAMP-mediated Signal Transduction via Interaction of Caveolins with the Catalytic Subunit of Protein Kinase A J. Biol. Chem., September 10, 1999; 274(37): 26353 - 26360. [Abstract] [Full Text] [PDF]

				A. Schlegel, R. B. Schwab, P. E. Scherer, and M. P. Lisanti A Role for the Caveolin Scaffolding Domain in Mediating the Membrane Attachment of Caveolin-1. THE CAVEOLIN SCAFFOLDING DOMAIN IS BOTH NECESSARY AND SUFFICIENT FOR MEMBRANE BINDING IN VITRO J. Biol. Chem., August 6, 1999; 274(32): 22660 - 22667. [Abstract] [Full Text] [PDF]

				C. Schwencke, M. Yamamoto, S. Okumura, Y. Toya, S.-J. Kim, and Y. Ishikawa Compartmentation of Cyclic Adenosine 3',5'-Monophosphate Signaling in Caveolae Mol. Endocrinol., July 1, 1999; 13(7): 1061 - 1070. [Abstract] [Full Text]

				V. O. Rybin, X. Xu, and S. F. Steinberg Activated Protein Kinase C Isoforms Target to Cardiomyocyte Caveolae : Stimulation of Local Protein Phosphorylation Circ. Res., May 14, 1999; 84(9): 980 - 988. [Abstract] [Full Text] [PDF]

				C. V. Carman, M. P. Lisanti, and J. L. Benovic Regulation of G Protein-coupled Receptor Kinases by Caveolin J. Biol. Chem., March 26, 1999; 274(13): 8858 - 8864. [Abstract] [Full Text] [PDF]

				K. A. Fagan, K. E. Smith, and D. M. F. Cooper Regulation of the Ca2+-inhibitable Adenylyl Cyclase Type VI by Capacitative Ca2+ Entry Requires Localization in Cholesterol-rich Domains J. Biol. Chem., August 18, 2000; 275(34): 26530 - 26537. [Abstract] [Full Text] [PDF]

				S. Schreiber, J. Fleischer, H. Breer, and I. Boekhoff A Possible Role for Caveolin as a Signaling Organizer in Olfactory Sensory Membranes J. Biol. Chem., July 28, 2000; 275(31): 24115 - 24123. [Abstract] [Full Text] [PDF]

				V. O. Rybin, X. Xu, M. P. Lisanti, and S. F. Steinberg Differential Targeting of beta -Adrenergic Receptor Subtypes and Adenylyl Cyclase to Cardiomyocyte Caveolae. A MECHANISM TO FUNCTIONALLY REGULATE THE cAMP SIGNALING PATHWAY J. Biol. Chem., December 22, 2000; 275(52): 41447 - 41457. [Abstract] [Full Text] [PDF]