Abstract
Intestinal magnesium (Mg) uptake is essential for systemic Mg homeostasis. Colon cells express the two highly homologous transient receptor potential melastatin type (TRPM) 6 and 7 Mg2+ channels, but their precise function and the consequences of their mutual interaction are not clear. To explore the functional role of TRPM6 and TRPM7 in the colon, we used human colon cell lines that innately express both channels and analyzed the functional consequences of genetic knocking-down, by RNA interference, or pharmacological inhibition, by NS8593, of either channel. TRPM7 silencing caused an increase in Mg2+ influx, and correspondingly enhanced cell proliferation and migration, while downregulation of TRPM6 did not affect significantly either Mg2+ influx or cell proliferation. Exposure to the specific TRPM6/7 inhibitor NS8593 reduced Mg2+ influx, and consequently cell proliferation and migration, but Mg supplementation rescued the inhibition. We propose a model whereby in colon cells the functional Mg2+ channel at the plasma membrane may consist of both TRPM7 homomers and TRPM6/7 heteromers. A different expression ratio between the two proteins may result in different functional properties. Altogether, our findings confirm that TRPM6 cannot be replaced by TRPM7, and that TRPM6/7 complexes and TRPM6/7-mediated Mg2+ influx are indispensable in human epithelial colon cells.
Highlights
Magnesium (Mg) is involved in virtually all major metabolic and signaling pathways in the cell, and disturbances of Mg homeostasis accompany a variety of diseases [1]
We assessed a panel of human colon cell lines (HT29, HCT116, RKO and CaCo2) for TRPM6
We assessed a panel of human colon cell lines (HT29, HCT116, RKO and Caco-2) for TRPM6 and TRPM7 protein expression using Western blot
Summary
Magnesium (Mg) is involved in virtually all major metabolic and signaling pathways in the cell, and disturbances of Mg homeostasis accompany a variety of diseases [1]. Systemic Mg homeostasis primarily depends on the concerted actions of the intestine responsible for Mg uptake from food, and the kidneys, that regulate urinary Mg excretion [1]. Classical physiological experiments with different animal species have identified two Mg transport systems in the intestinal epithelium: An active transcellular and a passive paracellular pathway [2,3]. The paracellular pathway, which is driven by the electrochemical gradient, is responsible for bulk Mg absorption and takes place mostly in the small intestine, whereas fine-tuning occurs in the cecum and colon via transcellular transport.
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