Differential effects of protein kinase C activation on 5-HT(1A) receptor coupling to Ca²⁺ and K⁺ currents in rat serotonergic neurones

1. Activation of the enzyme protein kinase C (PKC) partially uncouples receptors from the inhibition of Ca²⁺ current. We have studied the effect of PKC activation on 5-HT(1A) receptor coupling to Ca²⁺ currents and 5-HT-induced K⁺ current (I(K,5-HT)) in acutely isolated adult rat dorsal raphe neurones. 2. The phorbol ester 4β-phorbol 12-myristate, 13-acetate (PMA; 1 μM) did not significantly alter the peak Ca²⁺ current. A maximal dose of 5-HT inhibited Ca²⁺ current on average by 52%; after application of PMA, the inhibition was only 30% and the effect was irreversible for the duration of the experiment. 3. The inactive phorbol ester 4α-phorbol (1 μM) did not reduce the effectiveness of 5-HT. When the kinase inhibitor staurosporine (ST; 200 nM) was added, PMA reduced the effect of 5-HT by only 13.9%. ST partially prevented or reversed the effect of PMA, depending on the order of addition. 4. The voltage-dependent rate of re-inhibition by 5-HT was reduced by PMA, suggesting that fewer activated G-protein subunits are available to interact with the Ca²⁺ channel after the action of PMA. 5. In contrast, PMA (1 μM) did not have a significant effect on I(K,5-HT). 6. PKC activation has an inhibitory effect on one branch of the 5-HT(1A) receptor transduction fork, namely inhibition of Ca²⁺ influx, but not on the activation of I(K,5-HT).