Abstract
TRPM7 channels participate in a variety of physiological/pathological processes. TRPM7 currents are modulated by protons but opposing effects of external pH (pHo) (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 pHo 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 pHo in extracellular medium containing Ca2+ and Mg2+, but suppressed by acidic pHo in the absence of extracellular Ca2+ and Mg2+. The potentiating effect in the presence of extracellular divalents occurred at pHo below 6 and was voltage-dependent. The inhibitory effect in the absence of extracellular divalents was already marked at pHo 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 pHo. We demonstrate that proton-induced modification of TRPM7 currents depends on the presence of extracellular Ca2+ and Mg2+. Variability of the TRPM7 current density in human cardiomyocytes is related to the clinical history, being higher in atrial fibrillation and in ischemic cardiomyopathy.
Highlights
Mammalian cells express a diversity of transient receptor potential (TRP) channels, which underly a multitude of functions [1,2]
Both outward and inward currents increased with time before the removal of extracellular divalents, and a steady-state was reached after 20 min
We have previously shown that while the TRPM7 current was detectable in ventricular cardiomyocytes from various species only during cell dialysis with 0-mM [Mg2+]i pipette solution [9], measurable TRPM7 current can be detected in freshly isolated human atrial cardiomyocytes even with physiological [Mg2+]i [11]
Summary
Mammalian cells express a diversity of transient receptor potential (TRP) channels, which underly a multitude of functions [1,2]. The electrophysiological characterization of these or like channels in native cardiac cells has only involved very few studies [7,9,10,11,12,13]. This is due in particular to problems of separating currents carried by TRPM7 from those of different channels co-expressed in the same cell, for lack of specific inhibitors
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