Regulation of endogenous and heterologous Ca²⁺ release-activated Ca²⁺ currents by pH.
Regulation of endogenous and heterologous Ca²⁺ release-activated Ca²⁺ currents by pH.
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pH 对内源性和异源 Ca²⁺ 释放激活的 Ca²⁺ 电流的调控
DOI：
10.1016/j.ceca.2014.07.011
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发表时间：
2014-09
期刊：
影响因子：
4
通讯作者：
Peinelt C
中科院分区：
文献类型：
--
作者：
Beck A;Fleig A;Penner R;Peinelt C
偏离生理pH（~ pH 7.2）以及改变的Ca 2+信号传导在免疫疾病和癌症中起重要作用。钙库操纵的钙内流（SOCE）或钙释放激活的钙电流（ICRAC）是细胞内钙内流最普遍的途径之一，其在细胞内钙库耗尽时被激活。我们在这里表明，细胞外和细胞内pH值的变化调节Jurkat T淋巴细胞和RBL 2 H3细胞中的内源性ICRAC，以及表达分子组分STIM 1/2和Orai 1/2/3（CRACM 1/2/3）的HEK 293细胞中的异源性ICRAC。我们发现，外部酸化抑制，碱化促进IP 3诱导的ICRAC。在不存在IP 3的情况下，外部碱化不引起内源性ICRAC，但能够激活表达Orai 1/2/3和STIM 1或STIM 2的HEK 293细胞中的异源ICRAC。同样，内部酸化减少IP 3诱导的内源性和异源性ICRAC的激活，而碱化加速其激活动力学，而不影响整体电流幅度。两个天冬氨酸残基突变为不带电荷的丙氨酸氨基酸（D110/112 A）在第一个胞外环的Orai 1显着减弱ICRAC的抑制外部酸性pH值，以及其促进碱性条件。我们的结论是，内部和细胞外的pH值差异调节ICRAC。虽然细胞内pH可能影响STIM与奥赖的聚集和/或结合，但外部pH似乎通过其通道孔调节ICRAC，这在Orai 1中部分由残基D110和D112介导。
Deviations from physiological pH (~ pH 7.2) as well as altered Ca2+ signaling play important roles in immune disease and cancer. One of the most ubiquitous pathways for cellular Ca2+ influx is the store-operated Ca2+ entry (SOCE) or Ca2+ release-activated Ca2+ current (ICRAC), which is activated upon depletion of intracellular Ca2+ stores. We here show that extracellular and intracellular changes in pH regulate both endogenous ICRAC in Jurkat T lymphocytes and RBL2H3 cells, and heterologous ICRAC in HEK293 cells expressing the molecular components STIM1/2 and Orai1/2/3 (CRACM1/2/3). We find that external acidification suppresses, and alkalization facilitates IP3-induced ICRAC. In the absence of IP3, external alkalization did not elicit endogenous ICRAC but was able to activate heterologous ICRAC in HEK293 cells expressing Orai1/2/3 and STIM1 or STIM2. Similarly, internal acidification reduced IP3-induced activation of endogenous and heterologous ICRAC, while alkalization accelerated its activation kinetics without affecting overall current amplitudes. Mutation of two aspartate residues to uncharged alanine amino acids (D110/112A) in the first extracellular loop of Orai1 significantly attenuated both the inhibition of ICRAC by external acidic pH as well as its facilitation by alkaline conditions. We conclude that intra- and extracellular pH differentially regulates ICRAC. While intracellular pH might affect aggregation and/or binding of STIM to Orai, external pH seems to modulate ICRAC through its channel pore, which in Orai1 is partially mediated by residues D110 and D112.
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DOI：
10.1126/science.1228757
发表时间：
2012-12-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hou X;Pedi L;Diver MM;Long SB
通讯作者：
Long SB
DOI：
10.1085/jgp.111.4.521
发表时间：
1998-04
期刊：
The Journal of general physiology
影响因子：
--
作者：
Kerschbaum HH;Cahalan MD
通讯作者：
Cahalan MD
DOI：
10.1073/pnas.0806499105
发表时间：
2008-09-09
影响因子：
11.1
作者：
Ji, Wei;Xu, Pingyong;Chen, Liangyi
通讯作者：
Chen, Liangyi
DOI：
10.1016/j.bbamcr.2012.12.009
发表时间：
2013-03-01
影响因子：
5.1
作者：
Faouzi, Malika;Kischel, Philippe;Ouadid-Ahidouch, Halima
通讯作者：
Ouadid-Ahidouch, Halima
DOI：
10.1073/pnas.83.3.654
发表时间：
1986-02-01
影响因子：
11.1
作者：
IIJIMA, T;CIANI, S;HAGIWARA, S
通讯作者：
HAGIWARA, S