Ca2+ current facilitation is CaMKII-dependent and has arrhythmogenic consequences

被引:50
作者
Bers, Donald M. [1 ]
Morotti, Stefano [1 ]
机构
[1] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA
关键词
CaMKII; calcium channel; calcium current inactivation; calcium current facilitation; calcium current staircase; PROTEIN-KINASE-II; ACTION-POTENTIAL REPOLARIZATION; RABBIT VENTRICULAR MYOCYTES; CA(V)1.2 CALCIUM-CHANNEL; MAMMALIAN HEART-CELLS; SEE VOL. 593; CALMODULIN KINASE; SARCOPLASMIC-RETICULUM; CA2+-DEPENDENT INACTIVATION; RYANODINE RECEPTOR;
D O I
10.3389/fphar.2014.00144
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The cardiac voltage gated Ca2+ current (I-Ca) is critical to the electrophysiological properties, excitation-contraction coupling, mitochondrial energetics, and transcriptional regulation in heart. Thus, it is not surprising that cardiac I-Ca is regulated by numerous pathways. This review will focus on changes in I-Ca that occur during the cardiac action potential (AP), with particular attention to Ca2+-dependent inactivation (CDI), Ca2+-dependent facilitation (CDF) and how calmodulin (CaM) and Ca2+-CaM dependent protein kinase (CaMKII) participate in the regulation of Ca2+ current during the cardiac AP CDI depends on CaM pre-bound to the C-terminal of the L-type Ca2+ channel, such that Ca2+ influx and Ca2+ released from the sarcoplasmic reticulum bind to that CaM and cause CDI. In cardiac myocytes CDI normally pre-dominates over voltage-dependent inactivation. The decrease in I-Ca via CDI provides direct negative feedback on the overall Ca2+ influx during a single beat, when myocyte Ca2+ loading is high. CDF builds up over several beats, depends on CaMKII-dependent Ca2+ channel phosphorylation, and results in a staircase of increasing I-Ca peak, with progressively slower inactivation. CDF and CDI co-exist and in combination may fine-tune the I-Ca waveform during the cardiac AP CDF may partially compensate for the tendency for Ca2+ channel availability to decrease at higher heart rates because of accumulating inactivation. CDF may also allow some reactivation of I-Ca during long duration cardiac APs, and contribute to early afterdepolarizations, a form of triggered arrhythmias.
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页数:10
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