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 receptor s of the 5-hydroxytryptamine (5-HT)(4) subtype increases membrane exci tability by reducing the calcium-activated potassium current responsib le for the slow afterhyperpolarization observed in these cells. In the present study, the signaling mechanism by which 5-HT4 receptors reduc e the afterhyperpolarization in the CA1 region was examined using intr acellular recording in brain slices. Administration of the membrane-pe rmeable cAMP analog 8-bromo-cAMP mimicked the effect of serotonin on t he afterhyperpolarization, whereas administration of the protein kinas e inhibitor staurosporine inhibited the effects of serotonin. These ob servations suggested a role for protein kinase A in this response. Thi s was confirmed by intracellular injection of the selective protein ki nase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate ((Rp)-cA MPS), which noncompetitively inhibited the ability of serotonin to red uce the after-hyperpolarization. Additional evidence for the involveme nt 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 en hance a known cAMP-mediated response, a significant enhancement of the ability of 5-HT4 receptors to reduce the afterhyperpolarization was o bserved. Together, these results indicate that serotonin reduces the a fterhyperpolarization in the CA1 region by acting on 5-HT4 receptors t hat increase intracellular cAMP levels and activate protein kinase A.