Adenylyl cyclase P-site ligands accelerate differentiation in Ob1771 preadipocytes

Azeddine Ibrahimi, Nada Abumrad, Hengameh Maghareie, Michael Golia, Ilana Shoshani, Laurent Désaubry, Roger A. Johnson

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15 Scopus citations

Abstract

Differentiation of Ob1771 preadipocytes to adipocytes was characterized by morphological changes and elevated expression of the specific marker enzyme, glycerol-3-phosphate dehydrogenase. A differentiation response substantially more complete and rapid than that obtained with insulin and 3,5,3'-triiodothyronine was observed with established inhibitors of adenylyl cyclases: 2',5'-dideoxyadenosine (2',5'-dd-Ado), 9-(cyclopentyl)adenine (9- CP-Ade), and 9-(arabinofuranosyl)adenine (9-Ara-Ade), coincident with decreased cellular cAMP levels. These ligands inhibit adenylyl cyclases noncompetitively, via a domain referred to as the P-site because of its requirement for an intact purine moiety. Differentiation was not induced by inosine, a nucleoside known not to act at the P-site, or by N6-(2- phenylisopropyl)adenosine or 1,3-diethyl-8-phenylxanthine, agonist and antagonist, respectively, for adenosine A1 receptors. Also ineffective were IBMX or forskolin, agents that can raise intracellular cAMP levels. Potency of the differentiation response followed the order 2',5'-dd-Ado (1-20 μM) > 9-CP-Ade (10-100 μM) = 9-Ara-Ade (10-100 μM) >> inosine, consistent with their potencies to inhibit adenylyl cyclases. The data suggest that inhibition of adenylyl cyclase via the P-site and the consequent reduction in cell cAMP levels facilitate the induction of differentiation in Ob1771 cells. The findings raise the question whether the known endogenous P-site ligands participate in the differentiation response induced by hormones.

Original languageEnglish
Pages (from-to)C487-C496
JournalAmerican Journal of Physiology - Cell Physiology
Volume276
Issue number2 45-2
StatePublished - Mar 5 1999
Externally publishedYes

Keywords

  • 2',5'-dideoxyadenosine
  • 9- (cyclopentyl)adenine
  • Adenosine 3',5'-cyclic monophosphate
  • Adipocytes
  • P-site inhibition
  • Signal transduction

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    Ibrahimi, A., Abumrad, N., Maghareie, H., Golia, M., Shoshani, I., Désaubry, L., & Johnson, R. A. (1999). Adenylyl cyclase P-site ligands accelerate differentiation in Ob1771 preadipocytes. American Journal of Physiology - Cell Physiology, 276(2 45-2), C487-C496.