Protein phosphatase modulation of somatostatin receptor signaling in the mouse hippocampus.
Protein phosphatase modulation of somatostatin receptor signaling in the mouse hippocampus.
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DOI：
10.1016/j.neuropharm.2015.07.004
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发表时间：
2015-12
影响因子：
4.7
通讯作者：
Armstrong DL
中科院分区：
文献类型：
--
作者：
Lucas SJ;Armstrong DL
海马中的许多抑制性中间神经元释放神经肽生长抑素（SST），其通过Gi/Go偶联受体抑制神经元兴奋性。为了研究SST抑制海马神经元兴奋性的信号通路，我们对P14-P18小鼠急性脑切片中的CA 1锥体神经元进行了穿孔膜片钳记录。1 μM SST的水浴应用可逆地降低了响应去极化电流阶跃的动作电位放电频率，并与神经元超极化和膜电阻降低相关。这种作用是由钾通道介导的，具有KCNK样药理学作用。此外，在体外培养7天或更长时间的切片中，SST还产生动作电位放电的超极化非依赖性降低，当用fostriecin选择性抑制Ser/Thr蛋白磷酸酶PP 2A和PP 4时，也可以在急性切片中观察到。SST的这种超极化独立效应似乎是由G蛋白激活的内向整流K+（GIRK）通道介导的。通过Cre重组酶介导的floxed Ppp 5c基因的缺失敲低蛋白磷酸酶5，阻断SST的超极化非依赖性效应，并以与增加的SST受体脱敏一致的方式降低超极化依赖性效应。因此，可逆的蛋白磷酸化提供了一种机制，以增强或减少SST的抑制作用，这可能会允许系统水平的调节回路兴奋性在海马。
Many inhibitory interneurones in the hippocampus release the neuropeptide somatostatin (SST) which inhibits neuronal excitability through Gi/Go-coupled receptors. To investigate the signaling pathways underlying the SST inhibition of neuronal excitability in the hippocampus, we performed perforated patch-clamp recordings from CA1 pyramidal neurones in acute brain slices from P14-P18 mice. Bath application of 1 μM SST reversibly reduces the frequency of action potential firing in response to depolarising current steps, and is associated with neuronal hyperpolarisation and a reduction in membrane resistance. This effect is mediated by potassium channels with KCNK-like pharmacology. In addition, in slices that have been cultured in vitro for seven days or more, SST also produces a hyperpolarisation independent reduction in action potential firing, which can be also observed in acute slices when the Ser/Thr protein phosphatases PP2A and PP4 are inhibited selectively with fostriecin. This hyperpolarisation independent effect of SST appears to be mediated by G-protein activated inwardly rectifying K+ (GIRK) channels. Knockdown of protein phosphatase 5, by Cre recombinase mediated deletion of the floxed Ppp5c gene, blocks the hyperpolarisation independent effect of SST, and reduces the hyperpolarisation dependent effect in a manner consistent with increased SST receptor desensitisation. Thus, reversible protein phosphorylation provides a mechanism to enhance or diminish the inhibitory effect of SST, which could allow system level regulation of circuit excitability in the hippocampus.