Potentiation of 5-HT3 receptor-mediated responses by protein kinase C activation.
The effect of agents that activate or inhibit protein kinase C (PKC) on the function of recombinant 5-HT3 receptors expressed in Xenopus oocytes was studied. The PKC activator phorbol 12-myristate 13-acetate (PMA) induced a long-lasting increase in the amplitude of 5-HT-activated ion current. The potentiation was maximal at 20 min and had a duration of approximately 60 min. The inactive phorbol ester, 4 alpha-PMA, had no effect on 5-HT3 receptor-mediated current. The PMA-induced potentiation was concentration-dependent over the concentration range 0.1-300 nM. The percentage potentiation by PMA was maximal at low 5-HT concentrations and decreased with increasing concentrations of 5-HT. For current activated by 0.1 microM 5-HT, maximal potentiation (Emax) was 667% of control, the EC50 was 15 nM and the apparent Hill coefficient was 0.99. The PKC inhibitor, staurosporin, antagonized the PMA potentiation; whereas, inhibitors of protein kinase A (PKA) or tyrosine kinase had no effect on this potentiation. The observations show that PMA can potentiate 5-HT3 receptor-mediated responses and suggest that this potentiation is mediated by activation of PKC.
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014982:Xenopus laevis
D000470:Alkaloids; D004791:Enzyme Inhibitors; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate