June 17, 2014Open Access
Ca2+ current facilitation is CaMKII-dependent and has arrhythmogenic consequences
Key Result
CaMKII-dependent facilitation of L-type calcium channels increases calcium entry, contributing to intracellular calcium overload and the development of arrhythmogenic afterdepolarizations.
Structured PICO
P
Population
Cardiac myocytes and L-type Ca2+ channels (LTCC) in various experimental models (e.g., rabbit, guinea-pig, rat, mouse, heterologous cells)
CaMKII-dependent facilitation of L-type Ca2+ channels is a key regulatory mechanism of cardiac electrophysiology that can lead to arrhythmogenic consequences under pathophysiological conditions.
Limitations
- The detailed molecular mechanisms of CaMKII-dependent ICa facilitation remain to be fully resolved.
Abstract
The cardiac voltage gated Ca(2+) current (ICa) is critical to the electrophysiological properties, excitation-contraction coupling, mitochondrial energetics, and transcriptional regulation in heart. Thus, it is not surprising that cardiac ICa is regulated by numerous pathways. This review will focus on changes in ICa that occur during the cardiac action potential (AP), with particular attention to Ca(2+)-dependent inactivation (CDI), Ca(2+)-dependent facilitation (CDF) and how calmodulin (CaM) and Ca(2+)-CaM dependent protein kinase (CaMKII) participate in the regulation of Ca(2+) current during the cardiac AP. CDI depends on CaM pre-bound to the C-terminal of the L-type Ca(2+) channel, such that Ca(2+) influx and Ca(2+) 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 ICa via CDI provides direct negative feedback on the overall Ca(2+) influx during a single beat, when myocyte Ca(2+) loading is high. CDF builds up over several beats, depends on CaMKII-dependent Ca(2+) channel phosphorylation, and results in a staircase of increasing ICa peak, with progressively slower inactivation. CDF and CDI co-exist and in combination may fine-tune the ICa waveform during the cardiac AP. CDF may partially compensate for the tendency for Ca(2+) channel availability to decrease at higher heart rates because of accumulating inactivation. CDF may also allow some reactivation of ICa during long duration cardiac APs, and contribute to early afterdepolarizations, a form of triggered arrhythmias.