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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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

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Polyphosphates
Adenine
Nucleosides
Adenylyl Cyclases
Isoenzymes
Ligands
Derivatives
Adenosine
Inhibitory Concentration 50
Adenosine Triphosphate
Chemical activation
Tissue

ASJC Scopus subject areas

  • Biochemistry

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Isozyme-dependent sensitivity of adenylyl cyclases to P-site-mediated inhibition by adenine nucleosides and nucleoside 3'-polyphosphates. / Johnson, Roger A.; Désaubry, Laurent; Bianchi, Glen; Shoshani, Ilana; Lyons, Edward; Taussig, Ronald; Watson, Peter A.; Cali, James J.; Krupinski, John; Pieroni, Joseph P.; Iyengar, Ravi.

In: Journal of Biological Chemistry, Vol. 272, No. 14, 04.04.1997, p. 8962-8966.

Research output: Contribution to journalArticle

Johnson, RA, Désaubry, L, Bianchi, G, Shoshani, I, Lyons, E, Taussig, R, Watson, PA, Cali, JJ, Krupinski, J, Pieroni, JP & 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, vol. 272, no. 14, pp. 8962-8966. https://doi.org/10.1074/jbc.272.14.8962
Johnson, Roger A. ; Désaubry, Laurent ; Bianchi, Glen ; Shoshani, Ilana ; Lyons, Edward ; Taussig, Ronald ; Watson, Peter A. ; Cali, James J. ; Krupinski, John ; Pieroni, Joseph P. ; Iyengar, Ravi. / Isozyme-dependent sensitivity of adenylyl cyclases to P-site-mediated inhibition by adenine nucleosides and nucleoside 3'-polyphosphates. In: Journal of Biological Chemistry. 1997 ; Vol. 272, No. 14. pp. 8962-8966.
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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.",
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AU - Désaubry, Laurent

AU - Bianchi, Glen

AU - Shoshani, Ilana

AU - Lyons, Edward

AU - Taussig, Ronald

AU - Watson, Peter A.

AU - Cali, James J.

AU - Krupinski, John

AU - Pieroni, Joseph P.

AU - Iyengar, Ravi

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N2 - 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.

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