Abstract
Key points The role of plasma membrane Ca2+‐ATPase 1 (PMCA1) in Ca2+ homeostasis and electrical stability in atrial tissue has been investigated at both organ and cellular levels in mice with cardiomyocyte‐specific deletion of PMCA1 (PMCA1cko)The PMCA1cko hearts became more susceptible to atrial arrhythmic stress conditions than PMCA1loxP/loxP hearts.PMCA1 deficiency alters cellular Ca2+ homeostasis under both baseline and stress conditions.PMCA1 is required for maintaining cellular Ca2+ homeostasis and electrical stability in murine atria under stress conditions. To determine the role of plasma membrane Ca2+‐ATPase 1 (PMCA1) in maintaining Ca2+ homeostasis and electrical stability in the atrium under physiological and stress conditions, mice with a cardiomyocyte‐specific deletion of PMCA1 (PMCA1cko) and their control littermates (PMCA1loxP/loxP) were studied at the organ and cellular levels. At the organ level, the PMCA1cko hearts became more susceptible to atrial arrhythmias under rapid programmed electrical stimulation compared with the PMCA1loxP/loxP hearts, and such arrhythmic events became more severe under Ca2+ overload conditions. At the cellular level, the occurrence of irregular‐type action potentials of PMCA1cko atrial myocytes increased significantly under Ca2+ overload conditions and/or at higher frequency of stimulation. The decay of Na+/Ca2+ exchanger current that followed a stimulation protocol was significantly prolonged in PMCA1cko atrial myocytes under basal conditions, with Ca2+ overload leading to even greater prolongation. In conclusion, PMCA1 is required for maintaining Ca2+ homeostasis and electrical stability in the atrium. This is particularly critical during fast removal of Ca2+ from the cytosol, which is required under stress conditions.
Highlights
As one of the most crucial ions in the cell, Ca2+ is involved in cardiac electrophysiological activity, excitation–contraction coupling, contractile function, energy balance, cell death and gene transcription
We have begun to unravel the involvement of plasma membrane Ca2+-ATPase 1 (PMCA1) in atrial electrophysiology and Ca2+ homeostasis by studying a cardiomyocyte-specific deletion of PMCA1 in a mouse model
It is generally considered that plasma-membrane Ca2+-ATPase (PMCA) only make a minor contribution to Ca2+ efflux compared with Na+/Ca2+ exchanger (NCX) (Bers, 2000, 2002); several lines of evidence from this study indicate that PMCA1 is crucial for maintaining atrial Ca2+ homeostasis and electrical stability under stress conditions its role in Ca2+ extrusion under baseline physiological conditions is likely not significant
Summary
As one of the most crucial ions in the cell, Ca2+ is involved in cardiac electrophysiological activity, excitation–contraction coupling, contractile function, energy balance, cell death and gene transcription. During each action potential (AP) of cardiac myocytes, Ca2+ fluxes into the cell through voltage gated L-type Ca2+ channels (LTCCs), which are activated by AP-induced membrane depolarization. When contraction ends the Ca2+ ions are taken up by SERCA2a back into the SR, with the remainder being extruded by two outward transport mechanisms in the sarcolemma that are responsible for calcium extrusion: (i) the plasma-membrane Ca2+-ATPase (PMCA), which ejects calcium to the extracellular compartment using energy derived from ATP hydrolysis and is dependent on calmodulin (Bers, 2002), and (ii) the Na+/Ca2+ exchanger (NCX), which counter-transports 1 molecule of calcium in exchange for 3 molecules of sodium utilizing the sodium gradient across the plasma membrane as an energy source (Blaustein & Lederer, 1999).
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