Influence of pH on Ca²⁺ current and its control of electrical and Ca²⁺ signaling in ventricular myocytes.
Influence of pH on Ca²⁺ current and its control of electrical and Ca²⁺ signaling in ventricular myocytes.
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DOI：
10.1085/jgp.201110658
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Spitzer KW
中科院分区：
文献类型：
--
作者：
Saegusa N;Moorhouse E;Vaughan-Jones RD;Spitzer KW
心肌细胞中 H+ 离子对 L 型 Ca2+ 电流 (ICa,L) 的调节存在争议，据报道反应差异很大。在测量兔和豚鼠心室肌细胞的细胞内 Ca2+ (Ca2+i) 或 pHi（落射荧光显微镜）时，研究了 ICa,L 的 pH 敏感性（全细胞电压钳）。选择性降低细胞外或细胞内 pH（pHo 6.5 和 pHi 6.7）对 ICa,L 门控产生相反的影响，使稳态激活和失活曲线沿电压轴分别向右和向左移动。在低 pHo 下，这会降低 ICa,L，而在低 pHi 下，它会在钳位电位为负至 0 mV 时增加 ICa,L，尽管电流在更正的电位下会降低。当Ca2+i用BAPTA缓冲时，低pHi的刺激作用更加明显，基本上没有抑制作用。我们得出结论，细胞外 H+ 离子抑制，而细胞内 H+ 离子可以刺激 ICa,L。低 pHi 和 pHo 对 ICa,L 的影响是相加的，适当组合后往往会抵消。在抑制钙调蛋白激酶 II（使用 KN-93）后，它们仍然存在。效果与肌膜固定负电荷的 H+ 离子筛选一致，并通过 H+o 和 Ca2+i 进行额外的通道阻断。动作电位持续时间 (APD) 对 H+ 也很敏感，因低 pHo 而缩短，但因低 pHi 而延长，这主要是由 H+ 诱导的通过 L 型 Ca2+ 通道的晚期 Ca2+ 进入的变化引起的。 pH 敏感通道门控的动力学分析与全细胞建模相结合，成功预测了 APD 变化以及 Ca2+ 信号传导的许多伴随变化。我们得出的结论是，ICa,L 的 pHi 与 pHo 控制将对心脏酸碱紊乱期间的电信号和 Ca2+ 依赖性信号传导产生重大影响。
Modulation of L-type Ca2+ current (ICa,L) by H+ ions in cardiac myocytes is controversial, with widely discrepant responses reported. The pH sensitivity of ICa,L was investigated (whole cell voltage clamp) while measuring intracellular Ca2+ (Ca2+i) or pHi (epifluorescence microscopy) in rabbit and guinea pig ventricular myocytes. Selectively reducing extracellular or intracellular pH (pHo 6.5 and pHi 6.7) had opposite effects on ICa,L gating, shifting the steady-state activation and inactivation curves to the right and left, respectively, along the voltage axis. At low pHo, this decreased ICa,L, whereas at low pHi, it increased ICa,L at clamp potentials negative to 0 mV, although the current decreased at more positive potentials. When Ca2+i was buffered with BAPTA, the stimulatory effect of low pHi was even more marked, with essentially no inhibition. We conclude that extracellular H+ ions inhibit whereas intracellular H+ ions can stimulate ICa,L. Low pHi and pHo effects on ICa,L were additive, tending to cancel when appropriately combined. They persisted after inhibition of calmodulin kinase II (with KN-93). Effects are consistent with H+ ion screening of fixed negative charge at the sarcolemma, with additional channel block by H+o and Ca2+i. Action potential duration (APD) was also strongly H+ sensitive, being shortened by low pHo, but lengthened by low pHi, caused mainly by H+-induced changes in late Ca2+ entry through the L-type Ca2+ channel. Kinetic analyses of pH-sensitive channel gating, when combined with whole cell modeling, successfully predicted the APD changes, plus many of the accompanying changes in Ca2+ signaling. We conclude that the pHi-versus-pHo control of ICa,L will exert a major influence on electrical and Ca2+-dependent signaling during acid–base disturbances in the heart.
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DOI：
10.1085/jgp.200810143
发表时间：
2009-03
期刊：
The Journal of general physiology
影响因子：
--
作者：
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通讯作者：
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影响因子：
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作者：
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