Larkman P M, Kelly J S
Department of Pharmacology, University of Edinburgh, U.K.
Neuropharmacology. 1997 Apr-May;36(4-5):721-33. doi: 10.1016/s0028-3908(97)00021-x.
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.
5-羟色胺（5-HT）使成年和新生大鼠面部及脊髓运动神经元去极化，部分原因是增强了超极化激活的内向整流电流（IH）。在促进此作用的实验条件下，5-HT引发内向电流，该电流可被细胞内施加的3',5'-环磷酸腺苷（cAMP）模拟，并被cAMP特异性磷酸二酯酶抑制剂Ro 20-1724增强。在本研究中，我们表明5-HT的这一作用可被腺苷酸环化酶抑制剂2',3'-二脱氧腺苷（2',3'-DDA）、5'-腺苷亚胺二磷酸（AMP-PNP）和SQ-22536（9-(四氢-2-呋喃基)腺嘌呤）阻断，但不受蛋白激酶抑制剂H-7、星形孢菌素和白屈菜红碱的胞外或胞内应用影响。最近克隆的5-HT受体亚型5-HT4、5-HT6和5-HT7在激活时均能刺激腺苷酸环化酶。在存在胞内GTP-γ-S的情况下，5-HT不可逆地增强了IH。5-HT诱导的内向电流可被麦角新碱可逆性阻断，但不受5-HT4受体拮抗剂GR-113808A、5-HT6和5-HT7拮抗剂氯氮平以及5-HT1A拮抗剂WAY-100365的影响。5-甲氧基色胺（5-MeOT）和5-羧酰胺色胺（5-CT）模拟了5-HT的作用，其效价顺序为5-HT = 5MeOT > 5-CT。令人惊讶的是，8-羟基-2-(二-N-丙基氨基)-四氢萘（8-OH DPAT），一种5-HT1A和5-HT7激动剂，与报道的对脊髓运动神经元的激动剂作用不同，对面部运动神经元无活性。有人提出，5-HT介导的腺苷酸环化酶刺激产生的cAMP以不依赖磷酸化的方式，可能直接作用于IH通道。介导此反应的5-HT受体亚型与任何刺激腺苷酸环化酶的已分类5-HT受体亚型均无关联。
