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

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.