Bendahhou S, Cummins T R, Potts J F, Tong J, Agnew W S
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12003-7. doi: 10.1073/pnas.92.26.12003.
The adult skeletal muscle Na+ channel mu1 possesses a highly conserved segment between subunit domains III and IV containing a consensus protein kinase C (PKC) phosphorylation site that, in the neuronal isoform, acts as a master control for "convergent" regulation by PKC and cAMP-dependent protein kinase. It lacks an approximately 200-aa segment between domains I and II though to modulate channel gating. We here demonstrate that mu1 is regulated by PKC (but not cAMP-dependent protein kinase) in a manner distinct from that observed for the neuronal isoforms, suggesting that under the same conditions muscle excitation could be uncoupled from motor neuron input. Maximal phosphorylation by PKC, in the presence of phosphatase inhibitors, reduced peak Na+ currents by approximately 90% by decreasing the maximal conductance, caused a -15 mV shift in the midpoint of steady-state inactivation, and caused a slight speeding of inactivation. Surprisingly, these effects were not affected by mutation of the conserved serine (serine-1321) in the interdomain III-IV loop. the pattern of current suppression and gating modification by PKC resembles the response of muscle Na+ channels to inhibitory factors present in the serum and cerebrospinal fluid of patients with Guillain-Barré syndrome, multiple sclerosis, and idiopathic demyelinating polyradiculoneuritis.
成人骨骼肌钠离子通道μ1在亚基结构域III和IV之间有一个高度保守的片段，其中包含一个共有蛋白激酶C（PKC）磷酸化位点，在神经元亚型中，该位点作为PKC和环磷酸腺苷依赖性蛋白激酶“汇聚”调节的主要控制点。它在结构域I和II之间缺少一个约200个氨基酸的片段，该片段被认为可调节通道门控。我们在此证明，μ1受PKC（而非环磷酸腺苷依赖性蛋白激酶）调节，其调节方式与神经元亚型不同，这表明在相同条件下，肌肉兴奋可能与运动神经元输入解偶联。在存在磷酸酶抑制剂的情况下，PKC的最大磷酸化作用通过降低最大电导率使钠离子电流峰值降低约90%，使稳态失活中点负移15 mV，并使失活略有加速。令人惊讶的是，这些效应不受结构域III-IV环中保守丝氨酸（丝氨酸-1321）突变的影响。PKC对电流的抑制和门控修饰模式类似于肌肉钠离子通道对格林-巴利综合征、多发性硬化症和特发性脱髓鞘性多神经根神经炎患者血清和脑脊液中抑制因子的反应。
