Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels
Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels
复制标题
肽激素生长素释放肽通过抑制 Kv7/KCNQ 通道增强神经元兴奋性
DOI：
10.1038/ncomms2439
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发表时间：
2013-02-01
影响因子：
16.6
通讯作者：
Xie, Junxia
中科院分区：
文献类型：
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作者：
Shi, Limin;Bian, Xiling;Xie, Junxia
源自肠道的促食欲肽激素胃饥饿素可增强黑质致密部的神经元放电，而黑质致密部的多巴胺能神经元可调节黑质纹状体系统的功能以实现运动协调。在此，我们阐述一种新机制，即胃饥饿素通过其受体GHS - R1a抑制电压门控钾离子Kv7/KCNQ/M通道并激活PLC - PKC通路，从而增强黑质多巴胺能神经元的放电。对黑质致密部神经元的脑片记录显示，胃饥饿素可抑制内源性Kv7/KCNQ/M电流。GHS - R1a、PLC和PKC的选择性抑制剂可消除这种效应。在小鼠中通过转基因手段抑制内源性Kv7/KCNQ/M通道，或使用XE991阻断该通道，均可消除胃饥饿素诱导的神经元过度兴奋。在体内，脑室内注射胃饥饿素可使纹状体中多巴胺释放和转换增加。将胃饥饿素或XE991微量注射到黑质致密部会导致对侧出现肌张力障碍姿势，并减轻全身性给予D2受体拮抗剂氟哌啶醇所引发的僵住症。我们的研究结果表明，胃饥饿素/KCNQ信号通路很可能是神经系统常用的一条通路。
The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the substantia nigra pars compacta, where dopaminergic neurons modulate the function of the nigrostriatal system for motor coordination. Here we describe a novel mechanism by which ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway. Brain slice recordings of substantia nigra pars compacta neurons reveal that ghrelin inhibits native Kv7/KCNQ/M-currents. This effect is abolished by selective inhibitors of GHS-R1a, PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice or channel blockade with XE991 abolishes ghrelin-induced hyperexcitability.In vivo, intracerebroventricular ghrelin administration causes increased dopamine release and turnover in the striatum. Microinjection of ghrelin or XE991 into substantia nigra pars compacta results in contralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administration of the D2 receptor antagonist haloperidol. Our findings indicate that the ghrelin/KCNQ signalling is likely a common pathway utilized by the nervous system.