Inhibition by phenothiazine derivatives of the adenylate cyclase of amphibian oocytes.
The adenylate cyclase activity of membranes of Xenopus laevis oocytes and follicle cells was affected by the presence of 2-chloro-10-(3-aminopropyl)phenothiazine (CAPP) and two other antipsychotic drugs, fluphenazine and penfluridol. CAPP, at concentrations of 10 and 100 microM, had opposite effects on the activation of the oocyte adenylate cyclase by effectors that act through the G/F regulatory subunit. Under these conditions, the drug stimulated the activation by fluoride and drastically inhibited the activation by guanyl-5'-yl-imidodiphosphate [Gpp(NH)p] and by cholera toxin and GTP. The activity of the catalytic subunit measured in the presence of either Mn2+ or forskolin was not affected by 100 microM CAPP. however, concentrations of this drug above 100 microM inhibited the adenylate cyclase activated by fluoride or by forskolin and also inhibited the activity of a calmodulin-independent cyclic nucleotide phosphodiesterase present in the same oocyte membrane preparation. Oocyte adenylate cyclase has been shown previously to be inhibited by the hormone progesterone. The inhibitory effect of CAPP is additive to that measured with the hormone, indicating that these compounds act through different mechanisms. CAPP did not modify the concentration of Gpp(NH)p required to yield half-maximal activation and, although the drug inhibited more strongly at lower concentrations of Gpp(NH)p, saturating amounts of the guanine nucleotide did not reverse completely the inhibition caused by CAPP. The effects of these antipsychotic drugs on oocyte adenylate cyclase did not require the presence of free Ca2+ and were not altered by the addition of exogenous calmodulin and calcium.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002147:Calmodulin / Q000502:physiology; D002746:Chlorpromazine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D009865:Oocytes / Q000201:enzymology*; D014982:Xenopus laevis
D000067956:Adenylyl Cyclase Inhibitors; D014150:Antipsychotic Agents; D002147:Calmodulin; C022892:didemethylchlorpromazine; D006165:Guanylyl Imidodiphosphate; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D002118:Calcium; D002746:Chlorpromazine