Insight into the molecular regulation of the epithelial magnesium channel TRPM6

Abstract

Recent studies have greatly increased our knowledge concerning the molecular mechanisms of renal magnesium handling. This review highlights the functional features of the newly identified transient receptor potential channel melastatin subtype 6 (TRPM6), which forms the gatekeeper of active magnesium reabsorption in the kidney. TRPM6 confines a magnesium permeable channel of which the expression is regulated by multiple factors, including dietary magnesium, magnesiotropic hormones and drugs. TRPM6 channel activity is modulated by intracellular magnesium and pH. A recently identified point mutation in the pro-epidermal growth factor (EGF) gene, causing isolated recessive inherited renal hypomagnesemia, implicated EGF as a magnesiotropic hormone regulating TRPM6 activity. Furthermore, receptor for activated C-kinase (RACK1) was identified as the first associated protein of the TRPM6 alpha-kinase domain, which acts as a dynamic switch controlling TRPM6 activity in an auto-phosphorylation-dependent manner. Of note, the fused alpha-kinase domain functions as a sensor of the intracellular magnesium concentration and plays a feedback role in controlling TRPM6-mediated magnesium influx, preventing magnesium overload during epithelial magnesium transport. The diverse molecular regulation of TRPM6 by magnesiotropic hormones, intracellular factors and its fused alpha-kinase domain disclosed novel regulatory mechanisms of active magnesium reabsorption.