Effects of cyclosporine A on cyclic AMP generation and GTP-binding proteins in isolated islets.
The role of cyclosporine A (CsA) in cAMP generation and its relationship with guanine nucleotide-binding proteins (G-proteins) was investigated in isolated islets. cAMP accumulation in response to glucose, 3-isobutyl-1-methyl-xanthine (a phosphodiesterase inhibitor) and the calcium ionophore A23187 increased significantly (P less than 0.05) in the presence of 0.5 microgram/mL CsA. CsA (0.5 microgram/mL) was unable to affect the 2.1-fold increase in cAMP formation induced by 30 microM forskolin (an adenylate cyclase complex activator). The pertussis toxin-induced cAMP generation in the presence of 20 mM glucose was suppressed by CsA by 34%. On the other hand, CsA enhanced cAMP levels in cholera toxin-treated islets. CsA caused a non-competitive inhibition of phosphodiesterase activity with half-maximal inhibition at 5 micrograms/mL CsA. CsA blocked the pertussis toxin ADP-ribosylation of a 41-kDa and a 21-kDa islet protein, but not the cholera toxin ADP-ribosylation of a 45-kDa and a 21-kDa islet protein. These data indicate that CsA increases cAMP content by a non-competitive inhibition of phosphodiesterase activity and by acting through G-proteins involved in the modulation of adenylate cyclase activity. An inhibitory effect of CsA on a 21-kDa pertussis toxin-sensitive G-protein was also observed.
Martin
F
F
Department of Medical Biochemistry and Molecular Biology, School of Medicine, University of Seville, Spain.
Bedoya
F J
FJ
D037361:Adenylate Cyclase Toxin; D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D037342:Pertussis Toxin; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D010566:Virulence Factors, Bordetella; D016572:Cyclosporine; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D010727:Phosphoric Diester Hydrolases; D019204:GTP-Binding Proteins