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Volume 272, Number 14, Issue of April 4, 1997 pp. 8962-8966
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Isozyme-dependent Sensitivity of Adenylyl Cyclases to P-site-mediated Inhibition by Adenine Nucleosides and Nucleoside 3-Polyphosphates

(Received for publication, October 4, 1996, and in revised form, January 23, 1997)

Roger A. Johnson , Laurent Désaubry , Glen Bianchi , Ilana Shoshani , Edward Lyons Jr. , Ronald Taussig , Peter A. Watson ^** , James J. Cali ^** , John Krupinski ^** , Joseph P. Pieroni and Ravi Iyengar

From the  Department of Physiology and Biophysics, State University of New York, Health Sciences Center, Stony Brook, New York 11794-8661, the  Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, the ^** Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, and the  Department of Pharmacology, Mt. Sinai School of Medicine, City University of New York, New York, New York 10029-6574

Recombinant adenylyl cyclase isozyme Types I, II, VI, VII, and three splice variants of Type VIII were compared for their sensitivity to P-site-mediated inhibition by several adenine nucleoside derivatives and by the family of recently synthesized adenine nucleoside 3-polyphosphates (Désaubry, L., Shoshani, I., and Johnson, R. A. (1996) J. Biol. Chem. 271, 14028-14034). Inhibitory potencies were dependent on isozyme type, the mode of activation of the respective isozymes, and on P-site ligand. For the nucleoside derivatives potency typically followed the order 2,5-dideoxyadenosine (2,5-ddAdo) > -adenosine > 9-(cyclopentyl)-adenine (9-CP-Ade)  9-(tetrahydrofuryl)-adenine (9-THF-Ade; SQ 22,536), with the exception of Type II adenylyl cyclase, which was essentially insensitive to inhibition by 9-CP-Ade. For the adenine nucleoside 3-polyphosphates inhibitory potency followed the order Ado < 2-dAdo < 2,5-ddAdo and 3-mono- < 3-di- < 3-triphosphate. Differences in potency of these ligands were noted between isozymes. The most potent ligand was 2,5-dd-3-ATP with IC₅₀ values of 40-300 nM. The data demonstrate isozyme selectivity for some ligands, suggesting the possibility of isozyme-selective inhibitors to take advantage of differences in P-site domains among adenylyl cyclase isozymes. Differential expression of adenylyl cyclase isozymes may dictate the physiological sensitivity and hence importance of this regulatory mechanism in different cells or tissues.

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