Phorbol ester regulates stimulatory and inhibitory pathways of the hormone-sensitive adenylate cyclase system in rat reticulocytes.
Treatment of rat reticulocytes with tetradecanoyl phorbol acetate (TPA), a tumor-promoting phorbol ester which activates protein kinase C, resulted in an about 50% decrease in the stimulation of adenylate cyclase activity by a subsequent challenge with a beta-adrenoceptor agonist. This phenomenon mimics agonist-induced desensitization. This decline is due to a reduction in the Vmax of the adenylate cyclase system rather than to a change in affinity to the agonist. The beta-adrenoceptor number was not changed while the KD for an agonist but not for an antagonist was increased by TPA treatment. Prostaglandin E1 (PGE1) plus GTP, NaF plus AlCl3, and guanylyl-5'-imidodiphosphate (GppNHp) regulated adenylate cyclase activity in a biphasic manner, i.e. stimulation at lower concentrations and inhibition at higher concentrations. The same treatment also caused a dose- and time-dependent reduction of the inhibitory phase of the PGE1/GTP action but did not affect the inhibitory phase of GppNHp and NaF/AlCl3 actions. Pertussis toxin (IAP) treatment caused a reduction of the inhibitory phase of PGE1/GTP action similar to that caused by TPA treatment. No synergistic effect was observed when the cells were treated with TPA and IAP simultaneously. These results suggest that TPA treatment impairs the coupling between PGE1 receptor and Gi rather than enhances that between PGE1 receptor and Gs. Protein kinase C was involved in the regulation of hormone-sensitive adenylate cyclase, the beta-agonist-induced stimulatory pathway and the PGE1-induced inhibitory pathway in rat reticulocytes, since other phorbol esters and diacylglycerol, which activate this kinase, caused the same response.(ABSTRACT TRUNCATED AT 250 WORDS)
Yamashita
A
A
Department of Physiological Chemistry, Hiroshima University School of Medicine, Japan.
Kurokawa
T
T
Une
Y
Y
Ishibashi
S
S
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000097:blood*; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D037342:Pertussis Toxin; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D012156:Reticulocytes / Q000187:drug effects* / Q000201:enzymology; D012969:Sodium Fluoride / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D006165:Guanylyl Imidodiphosphate; D006160:Guanosine Triphosphate; D012969:Sodium Fluoride; D037342:Pertussis Toxin; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D000527:Alprostadil; D013755:Tetradecanoylphorbol Acetate