Molecular determinants of pH regulation in the cardiac Na(+)-Ca(2+) exchanger.
Molecular determinants of pH regulation in the cardiac Na(+)-Ca(2+) exchanger.
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DOI：
10.1085/jgp.201611693
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发表时间：
2018-02-05
期刊：
影响因子：
--
通讯作者：
Ottolia M
中科院分区：
文献类型：
--
作者：
John S;Kim B;Olcese R;Goldhaber JI;Ottolia M
细胞质质子抑制心脏 Na+–Ca2+ 交换器的分子机制尚不清楚。约翰等人利用诱变和电生理学。揭示了这种质膜转运蛋白内对 pH 调节很重要的特定残基。心脏 Na+–Ca2+ 交换器 (NCX) 在心脏中发挥着关键作用，每次收缩后都会排出 Ca2+，从而调节心脏收缩力。 NCX 的活性受到胞质质子的强烈抑制，这表明细胞内酸化将对心脏收缩力产生重要影响。然而，这种抑制作用的机制仍然难以捉摸。有人认为，pH 调节源于质子与 NCX 大细胞质环内两个 Ca2+ 结合域的竞争性结合，需要细胞内 Na+ 失活才能充分发育。通过结合诱变和电生理学，我们证明NCX pH调节是一种不同于Na+和Ca2+调节的变构机制，并且我们证明细胞质Na+可以影响NCX对质子的敏感性。我们进一步鉴定了对 NCX 质子敏感性很重要的两种组氨酸（His 124 和 His 165），并表明 His 165 起主导作用。我们的结果揭示了调节 NCX 活性的不同变构机制之间复杂的相互作用。由于 NCX 在心脏功能中发挥着核心作用，这些发现对于我们了解心脏病理生理学非常重要。
The molecular mechanisms underlying the inhibition of the cardiac Na+–Ca2+ exchanger by cytoplasmic protons are poorly defined. Using mutagenesis and electrophysiology, John et al. reveal specific residues within this plasma membrane transporter that are important for pH regulation. The cardiac Na+–Ca2+ exchanger (NCX) plays a critical role in the heart by extruding Ca2+ after each contraction and thus regulates cardiac contractility. The activity of NCX is strongly inhibited by cytosolic protons, which suggests that intracellular acidification will have important effects on heart contractility. However, the mechanisms underlying this inhibition remain elusive. It has been suggested that pH regulation originates from the competitive binding of protons to two Ca2+-binding domains within the large cytoplasmic loop of NCX and requires inactivation by intracellular Na+ to fully develop. By combining mutagenesis and electrophysiology, we demonstrate that NCX pH modulation is an allosteric mechanism distinct from Na+ and Ca2+ regulation, and we show that cytoplasmic Na+ can affect the sensitivity of NCX to protons. We further identify two histidines (His 124 and His 165) that are important for NCX proton sensitivity and show that His 165 plays the dominant role. Our results reveal a complex interplay between the different allosteric mechanisms that regulate the activity of NCX. Because of the central role of NCX in cardiac function, these findings are important for our understanding of heart pathophysiology.
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影响因子：
16
作者：
Hilge, M;Aelen, J;Vuister, GW
通讯作者：
Vuister, GW
影响因子：
4.8
作者：
Iwamoto, T;Uehara, A;Shigekawa, M
通讯作者：
Shigekawa, M
影响因子：
5.5
作者：
DOERING, AE;LEDERER, WJ
通讯作者：
LEDERER, WJ
心脏钠钙交换的稳态和动态特性。细胞质钙和ATP的次要调节。
DOI：
10.1085/jgp.100.6.933
发表时间：
1992-12
期刊：
The Journal of general physiology
影响因子：
--
作者：
Hilgemann DW;Collins A;Matsuoka S
通讯作者：
Matsuoka S
DOI：
10.1073/pnas.0902171106
发表时间：
2009-08-25
影响因子：
11.1
作者：
Hilge, Mark;Aelen, Jan;Vuister, Geerten W.
通讯作者：
Vuister, Geerten W.