Serotonin acting via cyclic AMP enhances both the hyperpolarizing and depolarizing phases of bursting pacemaker...

Bath application of 5-HT, at concentrations below 10 microM, enhances the amplitude of the interburst hyperpolarization in the Aplysia bursting pacemaker neuron R15. It is known that 5-HT acts via cyclic AMP to produce this effect by increasing the inwardly rectifying potassium current (IR). Here, we report that further elevating the concentration of 5-HT produces an enhancement of the depolarizing phase of the burst cycle that can eventually lead to tonic spiking activity. Voltage-clamp studies reveal that high concentrations of 5-HT continue to increase IR and, in addition enhance a voltage-gated inward current active near the action potential threshold. Pharmacological treatments and ion substitution experiments demonstrate that the inward current increased by high concentrations of 5-HT is a subthreshold calcium current (ICa). The 5-HT-induced increase in ICa is mimicked by bath application of the adenylate cyclase activator forskolin or injection of 8-bromo-cyclic AMP and is potentiated by the phosphodiesterase inhibitor isobutylmethylxanthine. It is concluded that 5-HT, acting via the second messenger cyclic AMP, can increase both potassium and calcium currents in neuron R15. It is also shown that the 5-HT-induced increase in these 2 opposing voltage-gated currents not only produces complex changes in bursting activity, but also dramatically alters R15's response to inhibitory and excitatory stimuli.