Modulation of IH by 5-HT in neonatal rat motoneurones in vitro: mediation through a phosphorylation independent action of cAMP.
The depolarization of adult and neonatal rat facial and spinal motoneurones by 5-hydroxytryptamine (5-HT) in part involves an enhancement of the hyperpolarization-activated, inward-rectifier, IH. Under experimental conditions which promote this action, 5-HT evokes an inward current which can be mimicked by intracellularly applied adenosine 3',5'-cyclic monophosphate (cAMP) and potentiated by the cAMP-specific phosphodiesterase inhibitor Ro 20-1724. In this study, we show that this action of 5-HT can be blocked by the adenylyl cyclase inhibitors 2'3'-dideoxyadenosine (2',3'-DDA). 5'-adenylimidodiphosphate (AMP-PNP) and SQ-22536 (9-(tetrahydro-2-furyl)adenine), but not by external or internal application of the protein kinase inhibitors H-7, staurosporine and chelerythrine. The most recently cloned 5-HT receptor subtypes, 5-HT4, 5-HT6 and 5-HT7, can all stimulate adenylyl cyclase when activated. In the presence of internal GTP-gamma-S, 5-HT irreversibly enhanced IH. The 5-HT-induced inward current could be reversibly blocked by methysergide, but not by the 5-HT4 receptor antagonist GR-113808A, the 5-HT6 and 5-HT7 antagonist clozapine and the 5-HT1A antagonist WAY-100365. 5-Methoxytryptamine (5-MeOT) and 5-carboxamidotryptamine (5-CT) mimicked the action of 5-HT with a rank order of potency of 5-HT = 5MeOT > 5-CT. Surprisingly, 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH DPAT), a 5-HT1A and 5-HT7 agonist was inactive on facial motoneurones unlike its reported agonist action on spinal motoneurones. It is proposed that cAMP produced by 5-HT-mediated stimulation of adenylyl cyclase acts in a phosphorylation-independent manner, possibly directly, on the IH channel. The 5-HT receptor subtype mediating this response cannot be correlated with any of the classified 5-HT receptor subtypes that stimulate adenylyl cyclase.
Larkman
P M
PM
Department of Pharmacology, University of Edinburgh, U.K. P.Larkman@ed.ac.uk
Kelly
J S
JS
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000963:Antimetabolites / Q000494:pharmacology; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D016048:Dideoxyadenosine / Q000494:pharmacology; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051381:Rats; D012701:Serotonin / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D000963:Antimetabolites; D007473:Ion Channels; D012701:Serotonin; D016048:Dideoxyadenosine; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases