Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability
Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability
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DOI：
10.1073/pnas.1204023109
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发表时间：
2012-07-10
影响因子：
11.1
通讯作者：
Foskett, J. Kevin
中科院分区：
文献类型：
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作者：
Ma, Zhongming;Siebert, Adam P.;Foskett, J. Kevin
细胞外Ca2+ (Ca-o(2+))在生理上起着重要作用。Ca-o（2+）浓度（[Ca2+](o)）的变化已被观察到在各种生理和病理生理环境下调节神经元的兴奋性，但神经元检测[Ca2+](o)的机制尚不完全清楚。钙稳态调节剂1 （CALHM1）表达可诱导细胞内的阳离子电流，提高细胞质Ca2+浓度（[Ca2+](i)），以响应Ca-o（2+）的去除及其随后的补充。然而，CALHM1是一个成孔离子通道还是调节内源性离子通道尚不清楚。在这里，我们发现CALHM1是质膜Ca2+渗透离子通道的成孔亚基，具有独特的离子渗透特性和独特的电压和[Ca2+](o)耦合变构门控调节。此外，我们发现CALHM1在小鼠皮质神经元中表达，通过增强电导和动作电位放电来响应减少[Ca2+](o)，并在Ca-o（2+）去除和添加时强烈升高[Ca2+](i)。相比之下，这些反应在CALHM1基因缺失小鼠的神经元中强烈减弱。这些结果表明，CALHM1是一个进化上保守的离子通道家族，可以检测膜电压和细胞外Ca2+水平，并在皮质神经元兴奋性和Ca2+稳态中发挥作用，特别是在降低[Ca2+](o)并恢复到正常水平时。
Extracellular Ca2+ (Ca-o(2+)) plays important roles in physiology. Changes of Ca-o(2+) concentration ([Ca2+](o)) have been observed to modulate neuronal excitability in various physiological and pathophysiological settings, but the mechanisms by which neurons detect [Ca2+](o) are not fully understood. Calcium homeostasis modulator 1 (CALHM1) expression was shown to induce cation currents in cells and elevate cytoplasmic Ca2+ concentration ([Ca2+](i)) in response to removal of Ca-o(2+) and its subsequent addback. However, it is unknown whether CALHM1 is a pore-forming ion channel or modulates endogenous ion channels. Here we identify CALHM1 as the pore-forming subunit of a plasma membrane Ca2+-permeable ion channel with distinct ion permeability properties and unique coupled allosteric gating regulation by voltage and [Ca2+](o). Furthermore, we show that CALHM1 is expressed in mouse cortical neurons that respond to reducing [Ca2+](o) with enhanced conductance and action potential firing and strongly elevated [Ca2+](i) upon Ca-o(2+) removal and its addback. In contrast, these responses are strongly muted in neurons from mice with CALHM1 genetically deleted. These results demonstrate that CALHM1 is an evolutionarily conserved ion channel family that detects membrane voltage and extracellular Ca2+ levels and plays a role in cortical neuronal excitability and Ca2+ homeostasis, particularly in response to lowering [Ca2+](o) and its restoration to normal levels.