5-HYDROXYTRYPTAMINE(4) RECEPTORS REDUCE AFTERHYPERPOLARIZATION IN HIPPOCAMPUS BY INHIBITING CALCIUM-INDUCED CALCIUM-RELEASE

Serotonin acting on 5-hydroxytryptamine(4) receptors increases membran e excitability in CA1 hippocampal pyramidal cells by reducing the slow calcium-activated afterhyperpolarization. This effect is mediated thr ough an increase in cAMP and activation of protein kinase A, although subsequent steps have not been elucidated. We now report that a signif icant portion of the calcium responsible for the generation of the aft erhyperpolarization originates from the release of intracellular calci um through a calcium-induced calcium-release mechanism. Thus, the afte rhyperpolarization is enhanced by caffeine, whereas it is inhibited by dantrolene and ruthenium red, two blockers of calcium-induced calcium release. The afterhyperpolarization is also inhibited by thapsigargin , which depletes intracellular calcium stores. These observations rais ed the possibility that serotonin might reduce the afterhyperpolarizat ion by regulating calcium-induced calcium release. Consistent with thi s possibility, administration of calcium-induced calcium-release block ers, as well as of thapsigargin, occluded the ability of serotonin to inhibit the afterhyperpolarization. Similarly, administration of caffe ine, which enhances the contribution of calcium-induced calcium releas e to the afterhyperpolarization, enhanced the effect of serotonin. The se results indicate that serotonin inhibits the afterhyperpolarization in the CA1 region of hippocampus by reducing the ability of extracell ular calcium to trigger calcium release from intracellular stores. As such, they identify a physiological role for the calcium-induced calci um release in hippocampus and provide evidence for its regulation by G protein-coupled receptors and, more specifically, 5-hydroxytryptamine (4) receptors.