Cyclic AMP and protein kinase A mediate 5-hydroxytryptamine type 4 receptor regulation of calcium-activated potassium current in adult hippocampal neurons.

In the CA1 region of the hippocampus, activation of serotonin receptors of the 5-hydroxytryptamine (5-HT)4 subtype increases membrane excitability by reducing the calcium-activated potassium current responsible for the slow afterhyperpolarization observed in these cells. In the present study, the signaling mechanism by which 5-HT4 receptors reduce the afterhyperpolarization in the CA1 region was examined using intracellular recording in brain slices. Administration of the membrane-permeable cAMP analog 8-bromo-cAMP mimicked the effect of serotonin on the afterhyperpolarization, whereas administration of the protein kinase inhibitor staurosporine inhibited the effects of serotonin. These observations suggested a role for protein kinase A in this response. This was confirmed by intracellular injection of the selective protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate ((Rp)-cAMPS), which noncompetitively inhibited the ability of serotonin to reduce the after-hyperpolarization. Additional evidence for the involvement of cAMP in the signaling by 5-HT4 receptors was obtained using the general phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. When this compound was bath administered at concentrations sufficient to enhance a known cAMP-mediated response, a significant enhancement of the ability of 5-HT4 receptors to reduce the afterhyperpolarization was observed. Together, these results indicate that serotonin reduces the afterhyperpolarization in the CA1 region by acting on 5-HT4 receptors that increase intracellular cAMP levels and activate protein kinase A.