Activity-dependent transcriptional regulation of M-Type (Kv7) K(+) channels by AKAP79/150-mediated NFAT actions.
Activity-dependent transcriptional regulation of M-Type (Kv7) K(+) channels by AKAP79/150-mediated NFAT actions.
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DOI：
10.1016/j.neuron.2012.10.019
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发表时间：
2012-12-20
期刊：
影响因子：
16.2
通讯作者：
Shapiro MS
中科院分区：
文献类型：
--
作者：
Zhang J;Shapiro MS
由KCNQ 2 -5（Kv 7）基因家族编码的M型K+通道在调节神经元兴奋性中起关键作用;然而，对其转录表达的控制机制知之甚少。在这里，我们发现了一种新的机制，调节KCNQ 2/3转录表达的神经元活动在啮齿类动物神经元，涉及激活钙调磷酸酶和核因子活化T细胞（NFAT）转录因子，编排的A-激酶锚定蛋白（AKAP）79/150。该信号需要通过L型Ca 2+通道的Ca 2+内流以及局部和全局Ca 2+升高。我们假设M通道表达的增加作为负反馈来抑制神经元的过度兴奋性，这一点可以通过药物诱导癫痫发作后野生型小鼠大脑中KCNQ 2/3转录的显著上调来证明，这种作用在AKAP 150 −/−小鼠中几乎被消除。因此，我们提出AKAP 79/150及其在活性依赖性M通道转录中组织的复合物的独特作用，这可能潜在地在整个神经系统中发挥作用，以限制与癫痫等疾病状态相关的过度兴奋。
M-type K+ channels, encoded by the KCNQ2-5 (Kv7) gene family, play key roles in regulation of neuronal excitability; however, less is known about the mechanisms controlling their transcriptional expression. Here, we discovered a novel mechanism regulating KCNQ2/3 transcriptional expression by neuronal activity in rodent neurons, involving activation of calcineurin and Nuclear Factor of Activated T-cells (NFAT) transcription factors, orchestrated by A-kinase-anchoring protein (AKAP)79/150. The signal requires Ca2+ influx through L-type Ca2+ channels and both local and global Ca2+ elevations. We postulate increased M-channel expression to act as a negative-feedback to suppress hyper-excitability of neurons, demonstrated by profoundly up-regulated KCNQ2/3 transcription in hippocampi from wild-type mice after drug-induced seizures, an effect nearly eliminated in AKAP150−/− mice. Thus, we suggest a distinct role of AKAP79/150 and the complex it organizes in activity-dependent M-channel transcription, which may potentially serve throughout the nervous system to limit over-excitability associated with disease states such as epilepsy.
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影响因子：
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