Cross-regulation between colocalized nicotinic acetylcholine and 5-HT3 serotonin receptors on presynaptic nerve terminals
Cross-regulation between colocalized nicotinic acetylcholine and 5-HT3 serotonin receptors on presynaptic nerve terminals
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DOI：
10.1038/aps.2009.62
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发表时间：
2009-06-01
影响因子：
8.2
通讯作者：
Nichols, Robert A.
中科院分区：
文献类型：
--
作者：
Dougherty, John J.;Nichols, Robert A.
目标：在脑中已经观察到功能独立的α 4烟碱乙酰胆碱受体和5-HT 3 5-羟色胺受体在突触前末梢上的大量共定位。本研究的目的是解决是否烟碱乙酰胆碱受体和5-HT 3 5-羟色胺受体在同一突触前末梢相互作用，表明胆碱能和多巴胺能调节的会聚。方法：在单个，分离的神经末梢纯化从大鼠纹状体钙反应采用共聚焦成像。结果：高选择性5-HT 3受体激动剂间氯苯双胍（100 nmol/L）持续刺激后，应用500 nmol/L尼古丁可显著降低Ca 2+反应（对照组的28%）仅在那些最初对间氯苯双胍有反应的纹状体神经末梢中。交叉调节在几分钟内发展。对间氯苯双胍没有反应的突触前神经末梢，表明5-HT 3受体不存在，对尼古丁表现出典型的反应。应用间氯苯双胍后，持续刺激尼古丁导致部分衰减的Ca 2+反应（49%的控制）。在用间氯苯双胍持续刺激后应用间氯苯双胍也导致Ca 2+反应的强烈衰减（对照组的12%），而尼古丁诱导的钙离子反应与尼古丁持续刺激后与对照组无显著差异。这些结果表明，突触前Ca 2+增加引起的5-HT 3受体或烟碱乙酰胆碱受体激活调节对5-HT 3受体激活的后续应答，但只有5-HT 3受体交叉调节随后的烟碱乙酰胆碱受体介导的应答。研究结果表明，在同一纹状体神经末梢的两个受体系统之间存在特定的相互作用，可能涉及在一个或多个水平上调节这些信号系统的Ca 2+依赖性细胞内途径。
Aim: Substantial colocalization of functionally independent alpha 4 nicotinic acetylcholine receptors and 5-HT3 serotonin receptors on presynaptic terminals has been observed in brain. The present study was aimed at addressing whether nicotinic acetylcholine receptors and 5-HT3 serotonin receptors interact on the same presynaptic terminal, suggesting a convergence of cholinergic and serotonergic regulation.Methods: Ca2+ responses in individual, isolated nerve endings purified from rat striatum were measured using confocal imaging.Results: Application of 500 nmol/L nicotine following sustained stimulation with the highly selective 5-HT3 receptor agonist m-chlorophenylbiguanide at 100 nmol/L resulted in markedly reduced Ca2+ responses (28% of control) in only those striatal nerve endings that originally responded to m-chlorophenylbiguanide. The cross-regulation developed over several minutes. Presynaptic nerve endings that had not responded to m-chlorophenylbiguanide, indicating that 5-HT3 receptors were not present, displayed typical responses to nicotine. Application of m-chlorophenylbiguanide following sustained stimulation with nicotine resulted in partially attenuated Ca2+ responses (49% of control). Application of m-chlorophenylbiguanide following sustained stimulation with m-chlorophenylbiguanide also resulted in a strong attenuation of Ca2+ responses (12% of control), whereas nicotine-induced Ca2+ responses following sustained stimulation with nicotine were not significantly different from control.Conclusion: These results indicate that the presynaptic Ca2+ increases evoked by either 5-HT3 receptor or nicotinic acetylcholine receptor activation regulate subsequent responses to 5-HT3 receptor activation, but that only 5-HT3 receptors cross-regulate subsequent nicotinic acetylcholine receptor-mediated responses. The findings suggest a specific interaction between the two receptor systems in the same striatal nerve terminal, likely involving Ca2+-dependent intracellular pathways that regulate these signaling systems at one or more levels.