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.
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, Missouri 63104.
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GE
Torres
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Y
Chaput
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Andrade
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004594:Electrophysiology; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D011985:Receptors, Serotonin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D019311:Staurosporine
D000470:Alkaloids; D015221:Potassium Channels; D011985:Receptors, Serotonin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019311:Staurosporine; D002118:Calcium