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Calcium modulation of cardiac sodium channels.
Journal of Physiology 2019 Februrary 2
Modification of voltage-gated Na+ channel (NaV ) function by intracellular Ca2+ has been a topic of much controversy. Early studies relied on measuring NaV function in the absence or presence of intracellular Ca2+ , and generated seemingly disparate results. Subsequent investigations revealed the mechanism(s) of Ca2+ -driven NaV modulation are complex and involve multiple accessory proteins. The Ca2+ -sensing protein calmodulin (CaM) has a central role in tuning NaV function to [Ca2+ ]i , but the mechanism has been obscured by other proteins (such as fibroblast growth factors (FGF) or CaM-dependent kinase II (CaMKII)) that can also modify channel function or exert an influence in a Ca2+ -dependent manner. Significant progress has been made in understanding the architecture of full-length ion channels and the structural and biophysical details of NaV -accessory protein interactions. Interdisciplinary structure-function studies are beginning to resolve the effect each interaction has on NaV gating. Carefully designed structure-guided or strategically selected disease-associated mutations are able to impair NaV -accessory protein interactions without altering other properties of channel function. Recently CaM was found to engage part of NaV 1.5 that is required for channel inactivation with high affinity. Careful impairment of this interaction disrupted NaV 1.5's ability to recover from inactivation. Such results support a paradigm of CaM-facilitated recovery from inactivation (CFRI). How NaV -CaM, CaMKII and FGF/fibroblast growth factor homologous factor interactions affect the timing or function of CFRI in cardiomyocytes remain open questions that are discussed herein. Moreover whether CFRI dysfunction or premature activation underlie certain NaV channelopathies are important questions that will require further investigation.
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