Grandi Eleonora, Herren Anthony W
Department of Pharmacology, University of California at Davis Davis, CA, USA.
Front Pharmacol. 2014 Mar 10;5:41. doi: 10.3389/fphar.2014.00041. eCollection 2014.
Na(+) homeostasis is a key regulator of cardiac excitation and contraction. The cardiac voltage-gated Na(+) channel, NaV1.5, critically controls cell excitability, and altered channel gating has been implicated in both inherited and acquired arrhythmias. Ca(2) (+)/calmodulin-dependent protein kinase II (CaMKII), a serine/threonine kinase important in cardiac physiology and disease, phosphorylates NaV1.5 at multiple sites within the first intracellular linker loop to regulate channel gating. Although CaMKII sites on the channel have been identified (S516, T594, S571), the relative role of each of these phospho-sites in channel gating properties remains unclear, whereby both loss-of-function (reduced availability) and gain-of-function (late Na(+) current, INa L) effects have been reported. Our review highlights investigating the complex multi-site phospho-regulation of NaV1.5 gating is crucial to understanding the genesis of acquired arrhythmias in heart failure (HF) and CaMKII activated conditions. In addition, the increased Na(+) influx accompanying INa L may also indirectly contribute to arrhythmia by promoting Ca(2) (+) overload. While the precise mechanisms of Na(+) loading during HF remain unclear, and quantitative analyses of the contribution of INa L are lacking, disrupted Na(+) homeostasis is a consistent feature of HF. Computational and experimental observations suggest that both increased diastolic Na(+) influx and action potential prolongation due to systolic INa L contribute to disruption of Ca(2) (+) handling in failing hearts. Furthermore, simulations reveal a synergistic interaction between perturbed Na(+) fluxes and CaMKII, and confirm recent experimental findings of an arrhythmogenic feedback loop, whereby CaMKII activation is at once a cause and a consequence of Na(+) loading.
钠（Na⁺）稳态是心脏兴奋和收缩的关键调节因子。心脏电压门控钠通道NaV1.5对细胞兴奋性起着至关重要的控制作用，通道门控的改变与遗传性和获得性心律失常均有关联。钙（Ca²⁺）/钙调蛋白依赖性蛋白激酶II（CaMKII）是一种在心脏生理和疾病中起重要作用的丝氨酸/苏氨酸激酶，它在第一个细胞内连接环内的多个位点使NaV1.5磷酸化，从而调节通道门控。尽管已确定通道上的CaMKII位点（S516、T594、S571），但这些磷酸化位点在通道门控特性中的相对作用仍不清楚，已有关于功能丧失（可用性降低）和功能获得（晚钠电流，INaL）效应的报道。我们的综述强调，研究NaV1.5门控的复杂多位点磷酸化调节对于理解心力衰竭（HF）和CaMKII激活状态下获得性心律失常的发生机制至关重要。此外，伴随INaL的钠（Na⁺）内流增加也可能通过促进钙（Ca²⁺）超载间接导致心律失常。虽然HF期间钠（Na⁺）负荷的确切机制尚不清楚，且缺乏对INaL贡献的定量分析，但钠（Na⁺）稳态破坏是HF的一个一致特征。计算和实验观察表明，舒张期钠（Na⁺）内流增加和收缩期INaL导致的动作电位延长均促成了衰竭心脏中钙（Ca²⁺）处理的破坏。此外，模拟揭示了受扰钠（Na⁺）通量与CaMKII之间的协同相互作用，并证实了最近关于致心律失常反馈环的实验发现，即CaMKII激活既是钠（Na⁺）负荷的原因又是结果。
