通过环磷酸腺苷依赖性蛋白激酶和蛋白激酶C对钠离子通道慢失活进行神经调节

Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C.

作者信息

Chen Yuan, Yu Frank H, Surmeier D James, Scheuer Todd, Catterall William A

机构信息

Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.

出版信息

Neuron. 2006 Feb 2;49(3):409-20. doi: 10.1016/j.neuron.2006.01.009.

DOI:10.1016/j.neuron.2006.01.009

PMID:16446144

Abstract

Neurotransmitters modulate sodium channel availability through activation of G protein-coupled receptors, cAMP-dependent protein kinase (PKA), and protein kinase C (PKC). Voltage-dependent slow inactivation also controls sodium channel availability, synaptic integration, and neuronal firing. Here we show by analysis of sodium channel mutants that neuromodulation via PKA and PKC enhances intrinsic slow inactivation of sodium channels, making them unavailable for activation. Mutations in the S6 segment in domain III (N1466A,D) either enhance or block slow inactivation, implicating S6 segments in the molecular pathway for slow inactivation. Modulation of N1466A channels by PKC or PKA is increased, whereas modulation of N1466D is nearly completely blocked. These results demonstrate that neuromodulation by PKA and PKC is caused by their enhancement of intrinsic slow inactivation gating. Modulation of slow inactivation by neurotransmitters acting through G protein-coupled receptors, PKA, and PKC is a flexible mechanism of cellular plasticity controlling the firing behavior of central neurons.

摘要

神经递质通过激活G蛋白偶联受体、环磷酸腺苷依赖性蛋白激酶（PKA）和蛋白激酶C（PKC）来调节钠通道的可用性。电压依赖性慢失活也控制着钠通道的可用性、突触整合和神经元放电。在这里，我们通过对钠通道突变体的分析表明，经由PKA和PKC的神经调节增强了钠通道的内在慢失活，使其无法激活。结构域III中S6片段的突变（N1466A、D）要么增强要么阻断慢失活，这表明S6片段参与了慢失活的分子途径。PKC或PKA对N1466A通道的调节增强，而对N1466D的调节几乎完全被阻断。这些结果表明，PKA和PKC的神经调节是由它们增强内在慢失活门控引起的。通过G蛋白偶联受体、PKA和PKC起作用的神经递质对慢失活的调节是一种灵活的细胞可塑性机制，可控制中枢神经元的放电行为。