KV7/M Channels Mediate Osmotic Modulation of Intrinsic Neuronal Excitability
KV7/M Channels Mediate Osmotic Modulation of Intrinsic Neuronal Excitability
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DOI：
10.1523/jneurosci.0942-09.2009
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发表时间：
2009-09-09
影响因子：
5.3
通讯作者：
Yaari, Yoel
中科院分区：
文献类型：
--
作者：
Caspi, Anna;Benninger, Felix;Yaari, Yoel
细胞外渗透压的适度降低可诱导大脑过度兴奋，最终导致癫痫发作。在细胞水平上，适度的低摩尔浓度显著增强了主要皮质神经元的内在兴奋性，而不显著影响它们的体积。低摩尔浓度最显著的细胞效应是将常规放电神经元转化为突发放电模式。这种效应是由去极化后的低渗促进作用（ADP）引起的，但其离子机制尚不清楚。由于神经元M型K+电流（K(V)7/M通道）下的K(V)7 （KCNQ）通道的阻滞剂也会导致ADP促进和破裂，我们假设降低渗透压抑制了这些通道。利用原位CA1锥体细胞的电流和电压钳记录，我们证实了这一假设。此外，我们表明，K(V)7/M通道的低渗抑制是由细胞内Ca2+浓度的增加介导的，通过释放内部储存，而不是通过细胞外Ca2+的内流。最后，我们发现干扰内部Ca2+介导的K(V)7/M通道的抑制完全可以防止低渗ADP的促进和破裂，表明这种新机制在低渗条件下产生内在的神经元高兴奋性的排他性。
Modest decreases in extracellular osmolarity induce brain hyperexcitability that may culminate in epileptic seizures. At the cellular level, moderate hyposmolarity markedly potentiates the intrinsic neuronal excitability of principal cortical neurons without significantly affecting their volume. The most conspicuous cellular effect of hyposmolarity is converting regular firing neurons to burst-firing mode. This effect is underlain by hyposmotic facilitation of the spike afterdepolarization (ADP), but its ionic mechanism is unknown. Because blockers of K(V)7 (KCNQ) channels underlying neuronal M-type K+ currents (K(V)7/M channels) also cause spike ADP facilitation and bursting, we hypothesized that lowering osmolarity inhibits these channels. Using current-and voltage-clamp recordings in CA1 pyramidal cells in situ, we have confirmed this hypothesis. Furthermore, we show that hyposmotic inhibition of K(V)7/M channels is mediated by an increase in intracellular Ca2+ concentration via release from internal stores but not via influx of extracellular Ca2+. Finally, we show that interfering with internal Ca2+-mediated inhibition of K(V)7/M channels entirely protects against hyposmotic ADP facilitation and bursting, indicating the exclusivity of this novel mechanism in producing intrinsic neuronal hyperexcitability in hyposmotic conditions.