Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy
Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy
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DOI：
10.1016/j.neuron.2004.07.014
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发表时间：
2004-08-05
期刊：
影响因子：
16.2
通讯作者：
Tsien, RW
中科院分区：
文献类型：
--
作者：
Cao, YQ;Piedras-Rentería, ES;Tsien, RW
几种人类通道病是由α（1A）突变引起的，α（1A）是P/Q型Ca 2+通道的成孔亚基，是诱发神经传递的突触前Ca 2+进入通道。我们发现，野生型人α（1A）亚基支持培养的小鼠海马神经元之间的传输以及内源性小鼠α（1A），而引入不渗透的人α（1A）阻碍了内源性亚基的作用。因此，突触前P/Q型通道可能会竞争限制其突触有效性的通道类型偏好“槽”。槽的存在产生的预测，神经传递可能会受到影响的Ca 2+通道特性的变化，我们通过研究与家族性偏瘫偏头痛1型（FHM 1）相关的α（1A）突变进行了测试。突变的人P/Q型通道在促进神经传递方面受损，与它们在支持全细胞Ca 2+通道活性方面的缺陷精确雅阁。野生型神经元中突变通道的表达减少了P/Q型通道的突触贡献，这表明对类型偏好槽的竞争可能支持FHM 1的显性遗传。
Several human channelopathies result from mutations in alpha(1A), the pore-forming subunit of P/Q-type Ca2+ channels, conduits of presynaptic Ca2+ entry for evoked neurotransmission. We found that wild-type human alpha(1A) subunits supported transmission between cultured mouse hippocampal neurons equally well as endogenous mouse alpha(1A), whereas introduction of impermeant human alpha(1A) hampered the effect of endogenous subunits. Thus, presynaptic P/Q-type channels may compete for channel type-preferring "slots" that limit their synaptic effectiveness. The existence of slots generates predictions for how neurotransmission might be affected by changes in Ca2+ channel properties, which we tested by studying alpha(1A) mutations that are associated with familial hemiplegic migraine type 1 (FHM1). Mutant human P/Q-type channels were impaired in contributing to neurotransmission in precise accord with their deficiency in supporting whole-cell Ca2+ channel activity. Expression of mutant channels in wild-type neurons reduced the synaptic contribution of P/Q-type channels, suggesting that competition for type-preferring slots might support the dominant inheritance of FHM1.