Isozyme-dependent sensitivity of adenylyl cyclases to P-site-mediated inhibition by adenine nucleosides and nucleoside 3'-polyphosphates

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

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91 Scopus citations

Abstract

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 (Desaubry, 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) > β-adenosine > 9-(cyclopentyl)-adenine (9- CP-Ade) ≤ 9-(tetrahydrofuryl)-adenine (9-TRF-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.

Original languageEnglish (US)
Pages (from-to)8962-8966
Number of pages5
JournalJournal of Biological Chemistry
Volume272
Issue number14
DOIs
StatePublished - Apr 4 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Johnson, R. A., Désaubry, L., Bianchi, G., Shoshani, I., Lyons, E., Taussig, R., Watson, P. A., Cali, J. J., Krupinski, J., Pieroni, J. P., & Iyengar, R. (1997). Isozyme-dependent sensitivity of adenylyl cyclases to P-site-mediated inhibition by adenine nucleosides and nucleoside 3'-polyphosphates. Journal of Biological Chemistry, 272(14), 8962-8966. https://doi.org/10.1074/jbc.272.14.8962