Alteration of the GTP-dependent inhibitory pathway of rat striatal adenylate cyclase by phorbol esters.
In membranes of rat striatum, phorbol 12-myristate 13-acetate (PMA), a potent activator of Ca2+/phospholipid-dependent protein kinase, enhanced adenylate cyclase activity by counteracting the inhibition elicited by GTP. Exposure to pertussis toxin caused a similar alteration of the GTP-regulation of the enzyme activity and largely prevented the PMA effects. PMA treatment increased by threefold the GTP requirement of acetylcholine-induced inhibition of adenylate cyclase activity but did not affect the GTP-dependence of the enzyme stimulation by dopamine. The hydrolysis of GTP by membrane-bound high affinity GTPase was significantly inhibited by PMA (IC 50 10 nM) in a Ca2(+)-dependent manner. Like PMA, phorbol 12,13-dibutyrate inhibited the GTPase activity, whereas the biologically inactive 4-beta phorbol 13-acetate and 4-beta phorbol were without effect. These results suggest that activation of Ca2+/phospholipid-dependent protein kinase by PMA stimulates adenylate cyclase activity by impairing the activity of the GTP-dependent inhibitory protein, possibly through a reduction of the GTP-GDP exchange.
Olianas
M C
MC
Department of Neurosciences, University of Cagliari, Italy.
Onali
P
P
D037361:Adenylate Cyclase Toxin; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000187:drug effects*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000502:physiology*; D006868:Hydrolysis; D008297:Male; D037342:Pertussis Toxin; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D000067956:Adenylyl Cyclase Inhibitors; D010566:Virulence Factors, Bordetella; D015240:Phorbol 12,13-Dibutyrate; D006160:Guanosine Triphosphate; D037342:Pertussis Toxin; D020558:GTP Phosphohydrolases; D000262:Adenylyl Cyclases; D013755:Tetradecanoylphorbol Acetate