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 ∼60 min. The inactive phorbol ester, 4α-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 μ 5-HT, maximal potentiation (E_max) 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.