DIFFERENTIAL-EFFECTS OF PROTEIN-KINASE-C ACTIVATION ON 5-HT1A RECEPTOR COUPLING TO CA2+ AND K+ CURRENTS IN RAT SEROTONERGIC NEURONS

1. Activation of the enzyme protein kinase C (PKC) partially uncouples receptors from the Is inhibition of Ca2+ current. We have studied the effect of PKC activation on 5-HT1A receptor coupling to Ca2+ currents and 5-HT-induced K+ current (I-K,I-5-HT) in acutely isolated adult ra t dorsal raphe neurones. 2. The phorbol ester 4 beta-phorbol 12-myrist ate, 13-acetate (PMA; 1 mu M) did not significantly alter the peak Ca2 + current. A maximal dose of 5-HT inhibited. Ca2+ current on average b y 52%; after application of PMA, the inhibition was only 30% and the e ffect was irreversible for the duration of the experiment. 3. The inac tive phorbol ester 4 alpha-phorbol (1 mu M) did not reduce the effecti veness of 5-HT. When the kinase inhibitor staurosporine (ST; 200 nM) w as added, PMA reduced the effect of 5-HT by only 13.9%. ST partially p revented or reversed the effect of PMA, depending on the order of addi tion. 4. The voltage-dependent rate of re-inhibition by 5-HT was reduc ed by PMA, suggesting that fewer activated G-protein subunits are avai lable to interact with the Ca2+ channel after the action of PMA. 5. In contrast, PMA (1 mu M) did not have a significant effect on I-K,I-5-H T. 6. PKC activation has an inhibitory effect on one branch of the 5-H T1A receptor transduction fork, namely inhibition of Ca2+ influx, but not on the activation of I-K,I-5-HT.