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

Date Published: January 27, 2017

Publisher: Public Library of Science

Author(s): Regina Mačianskienė, Mantė Almanaitytė, Aistė Jekabsone, Kanigula Mubagwa, Agustín Guerrero-Hernandez.


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.

Partial Text

Mammalian cells express a diversity of transient receptor potential (TRP) channels, which underly a multitude of functions [1,2]. Among these channels, TRPM7 (transient receptor potential melastatin 7) appears to be ubiquitously expressed, with highest expression in tissues such as the heart [3,4]. In the last decade, molecular biology and immunodetection techniques have been used successfully to demonstrate the expression of TRPM7 at the gene and protein levels in the heart [5–7], including during embryonic development [8]. At the same time, however, the electrophysiological characterization of these or like channels in native cardiac cells has only involved very few studies [7,9–13]. 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.

The study was carried out in accordance with the European Community guiding principles outlined in the Declaration of Helsinki, and was approved by the Ethics Committee of Biomedical Research of Kaunas Region, Lithuania (2014-05-23, Nr.BE-2-21).

TRPM7 channels are known to be inhibited by intracellular Mg2+, hence their electrophysiological identification usually involves dialyzing cells with low free Mg2+ concentrations ([Mg2+]i). Fig 1A shows the time evolution of whole-cell currents measured at +80 mV and –120 mV while dialyzing with 0-mM [Mg2+]i pipette solution, in either the presence or the absence of extracellular divalent cations. Both outward and inward currents increased with time before the removal of extracellular divalents, and a steady-state was reached after 20 min. The currents in the presence of extracellular Ca2+ and Mg2+ were small, due to voltage-dependent permeation block by the extracellular divalents [9,34]. Omitting divalent cations from the Tyrode solution rapidly and reversibly enlarged the outward and inward currents, consistent with large monovalent cation current flows under these conditions [3,9,35,36]. High [Mg2+]o (7.2 mM) decreased both outward and inward currents.

Interest in TRPM7 channels has increased recently following the discovery that these channels participate in a variety of physiological/pathophysiological processes (see Introduction). However TRPM7 channel function varies depending on cell type [9,38,39]. In view of the scarcity of electrophysiological data on TRPM7 in myocardiac cells, and given the potential importance of these channels, we focussed our study on human atrial cells. Given the importance of pH changes under pathological conditions such as ischemia, and since opposite effects have been reported for the effect of extracellular acidosis, we sought to investigate the modulation of TRPM7 by acidic pHo in human atrial cardiomyocytes. Our data demonstrate that both the inward and outward components of the TRPM7 current could be potentiated by an acidic pHo. Such proton-induced potentiation directly depends on presence of Ca2+ and Mg2+ in the extracellular medium, since the removal of these divalent cations caused a loss of the potentiation, replaced by the opposite effect, i.e. suppression of the TRPM7 current by extracellular acidification. Our data also suggest that the density of the TRPM7 current in human atrial cardiomyocytes highly depends on the underlying pathology, being higher in cells from patients with AF, especially those with history of coronary artery disease.

The effect of an acidic pHo on the TRPM7 current depends strongly on the presence or absence divalent cations in the extracellular milieu: potentiation by acidic pHo in extracellular medium containing Ca2+ and Mg2+, inhibition in nominally divalent-free environment. TRPM7 current magnitude is variable among human atrial cardiomyocytes, and a large part of this variability may be caused by the underlying cardiac pathology.

Samples used in the present study came from inhomogeneous groups of patients. Even within a group such as that of patients with history of ischemic cardiomyopathy, differences in medications will exist. In addition the level of remodelling (e.g. compensatory hypertrophy) as well as co-morbidities due aging or other pathologies and inflammation may vary within a group, with possible influence on TRPM7 channel expression/modulation. Data from very large groups of patients may be needed before any observed change can be accurately linked with a given pathology.




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