Modulation of Human Cardiac TRPM7 Current by Extracellular Acidic pH Depends upon Extracellular Concentrations of Divalent Cations

TRPM7 channels participate in a variety of physiological/pathological processes. TRPM7 currents are modulated by protons but opposing effects of external pH (pH(o)) (potentiation vs inhibition) have been reported. TRPM7 has been less studied in human cardiomyocytes than in heart-derived non-cardiomyocyte cells. We used the whole-cell patch-clamp technique on isolated human atrial cardiomyocytes to investigate the impact of an acidic pH(o) on the TRPM7 current. With voltage-dependent and other ion channels inhibited, cardiomyocytes were challenged with external acidification in either the presence or the absence of extracellular divalent cations. TRPM7 outward and inward currents were increased by acidic pH(o) in extracellular medium containing Ca(2+) and Mg(2+), but suppressed by acidic pH(o) in the absence of extracellular Ca(2+) and Mg(2+). The potentiating effect in the presence of extracellular divalents occurred at pH(o) below 6 and was voltage-dependent. The inhibitory effect in the absence of extracellular divalents was already marked at pH(o) of 6 and was practically voltage-independent. TRPM7 current density was higher in cardiomyocytes from patients with history of coronary vascular disease and the difference compared to cardiomyocytes from patients without history of myocardial ischemia increased with acidic pH(o). We demonstrate that proton-induced modification of TRPM7 currents depends on the presence of extracellular Ca(2+) and Mg(2+). Variability of the TRPM7 current density in human cardiomyocytes is related to the clinical history, being higher in atrial fibrillation and in ischemic cardiomyopathy.