Key result
Increasing intracellular Mg(2+) from 0.2 to 2 mM in the presence of PKA significantly decreased L-type Ca(2+) channel current by 70% in late-stage and 36% in early-stage differentiating cardiomyocytes.
Intracellular magnesium differentially regulates L-type calcium channel activity in developing iPSC-derived cardiomyocytes, confirming its role in modulating channel phosphorylation.
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Remains preclinical only; leaves open magnesium's regulatory role in human cardiomyocyte development.
Intracellular Mg(2+), which is implicated in arrhythmogenesis and transient cardiac ischemia, inhibits L-type Ca(2+) calcium channel current (ICaL) of adult cardiomyocytes (CMs). We take the advantage of an in vitro model of CMs based on induced pluripotent stem cells to investigate the effects of intracellular Mg(2+) on the phosphorylation or dephosphorylation processes of L-type Ca(2+) channels (LTCCs) at early and late stages of cardiac cell differentiation. Using the whole-cell patch-clamp technique, we demonstrate that increasing intracellular Mg(2+) concentration [Mg(2+)]i from 0.2 to 5 mM markedly reduced the peak of ICaL density, showing less effect on both the activation and inactivation properties in the late differentiation stage (LDS) of CMs more so than in the early differentiation stage (EDS). Increasing the [Mg(2+)]i from 0.2 to 2 mM in the presence of cAMP-dependent protein kinase A significantly decreased ICaL in LDS (70%) and in EDS (36%) CMs. In addition, the effect of forskolin was greatly attenuated in the presence of 2 mM [Mg(2+)]i in LDS but not in EDS CMs. The effect of forskolin was enhanced in the presence of ATP-γ-S in LDS CMs compared with EDS CMs. The exposure of both EDS and LDS CMs to 2 mM [Mg(2+)]i considerably reduced the effects of isobutylmethylxanthine (IBMX) and okadaic acid on ICaL. Our results provide evidence for differential regulation of LTCCs activities by cytosolic Mg(2+) concentration in developing cardiac cells and confirm that Mg(2+) acts under conditions that favor opening of the LTCCs caused by channel phosphorylation.
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Nguemo et al. (2014) studied this question. Intracellular Mg(2+) vs. 0.2 mM [Mg(2+)]i was evaluated on L-type Ca(2+) channel current (ICaL) density. Increasing intracellular Mg(2+) from 0.2 to 2 mM in the presence of PKA significantly decreased L-type Ca(2+) channel current by 70% in late-stage and 36% in early-stage differentiating cardiomyocytes.
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