PDF(Pubmed)
Abstract：
Vasoactive intestinal peptide (VIP) is an important component of the suprachiasmatic nucleus (SCN) which relays circadian information to neuronal populations, including GnRH neurons. Human and animal studies have shown an impact of disrupted daily rhythms (chronic shift work, temporal food restriction, clock gene disruption) on both male and female reproduction and fertility. To date, how VIP modulates GnRH neurons remains unknown. Calcium imaging and electrophysiology on primary GnRH neurons in explants and adult mouse brain slice, respectively, were used to address this question. We found VIP excites GnRH neurons via the VIP receptor, VPAC2. The downstream signaling pathway uses both Gs protein/adenylyl cyclase/protein kinase A (PKA) and phospholipase C/phosphatidylinositol 4,5-bisphosphate (PIP2) depletion. Furthermore, we identified a UCL2077-sensitive target, likely contributing to the slow afterhyperpolarization current (IAHP), as the PKA and PIP2 depletion target, and the KCa3.1 channel as a specific target. Thus, VIP/VPAC2 provides an example of Gs protein-coupled receptor-triggered excitation in GnRH neurons, modulating GnRH neurons likely via the slow IAHP. The possible identification of KCa3.1 in the GnRH neuron slow IAHP may provide a new therapeutical target for fertility treatments.
摘要：
血管活性肠肽（VIP）是视交叉上核（SCN）的重要组成部分，它将昼夜节律信息传递给神经元群体，包括GnRH神经元。人类和动物研究表明，日常节奏被打乱（慢性轮班工作，临时食物限制，时钟基因破坏）对男性和女性的生殖和生育能力。迄今为止,VIP如何调节GnRH神经元仍然未知。外植体和成年小鼠脑片中原代GnRH神经元的钙成像和电生理学，分别,被用来解决这个问题。我们发现VIP通过VIP受体刺激GnRH神经元,VPAC2.下游信号通路使用Gs蛋白/腺苷酸环化酶/蛋白激酶A（PKA）和磷脂酶C/磷脂酰肌醇4,5-二磷酸（PIP2）消耗。此外，我们确定了一个UCL2077敏感目标，可能导致缓慢的超极化后电流(IAHP)，作为PKA和PIP2消耗靶标，和KCa3.1通道作为特定的目标。因此，VIP/VPAC2提供了Gs蛋白偶联受体触发的GnRH神经元兴奋的例子，可能通过缓慢的IAHP调节GnRH神经元。GnRH神经元慢IAHP中KCa3.1的可能鉴定可能为生育治疗提供新的治疗靶标。
