Familial hemiplegic migraine mutations change α1A Ca2+ channel kinetics
Familial hemiplegic migraine mutations change α1A Ca2+ channel kinetics
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DOI：
10.1074/jbc.273.10.5586
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发表时间：
1998-03-06
影响因子：
4.8
通讯作者：
Striessnig, J
中科院分区：
文献类型：
--
作者：
Kraus, RL;Sinnegger, MJ;Striessnig, J
人类神经元P/Q型钙通道形成孔的α(1A)亚单位错义突变与家族性偏瘫(FHM)有关。这些突变的病理生理后果尚不清楚。我们将已报道的人类α(1A)亚基的四个单一突变引入到保守的兔α(1A)基因(R192Q、T666M、V714A和I1819L)中，并研究了突变体T666M、V714A和I1819L功能表达后通道功能的变化。突变体T666M、V714A和I1819L的通道门控发生了变化，而R192Q则没有。突变体T666M和V714A的Ba2+电流(I-BA)失活略快于野生型。T666M的通道失活恢复时间比野生型慢，V714A和I1819L的恢复快。因此，在1-HZ脉冲序列期间，通道失活累积对于突变体T666M更为明显，而对于V714A和I1819A则不那么明显。我们的数据表明，四个FHM突变中的三个位于可能的通道孔，改变了失活门控，并为FHM患者可能的神经元不稳定提供了病理生理学基础。
Missense mutations in the pore-forming human alpha(1A) subunit of neuronal P/Q-type Ca2+ channels are associated with familial hemiplegic migraine (FHM). The pathophysiological consequences of these mutations are unknown. We have introduced the four single mutations reported for the human alpha(1A) subunit into the conserved rabbit alpha(1A) (R192Q, T666M, V714A, and I1819L) and investigated possible changes in channel function after functional expression of mutant subunits in Xenopus laevis oocytes.Changes in channel gating were observed for mutants T666M, V714A, and I1819L but not for R192Q, Ba2+ current (I-Ba) inactivation was slightly faster in mutants T666M and V714A than in wild type. The time course of recovery from channel inactivation was slower than in wild type in T666M and accelerated in V714A and I1819L. As a consequence, accumulation of channel inactivation during a train of 1-Hz pulses was more pronounced for mutant T666M and less pronounced for V714A and I1819A. Our data demonstrate that three of the four FHM mutations, located at the putative channel pore, alter inactivation gating and provide a pathophysiological basis for the postulated neuronal instability in patients with FHM.