TRPM6 and TRPM7: A Mul-TRP-PLIK-cation of channel functions

Abstract

Unique among ion channels, TRPM6 and TRPM7 garnered much interest upon their discovery as the first ion channels to possess their own kinase domain. Soon after their identification, the two proteins were quickly linked to the regulation of magnesium homeostasis. However, study of their physiological functions in mouse and zebrafish have revealed expanding roles for these channel-kinases that include skeletogenesis and melanopore formation, thymopoiesis, cell adhesion, and neural fold closure during early development. In addition, mutations in the TRPM6 gene constitute the underlying genetic defect in hypomagnesemia with secondary hypocalcemia, a rare autosomal-recessive disease characterized by low serum magnesium accompanied by hypocalcemia. Depletion of TRPM7 expression in brain, on the other hand, proved successful in mitigating much of the cellular devastation that accompanies oxygen-glucose deprivation during ischemia. The aim of this review is to summarize the data emerging from molecular genetic, biochemical, electrophysiological, and pharmacological studies of these unique channel-kinases.

Fig. 1

Domain Structure and Current-Voltage Relationship of TRPM6 & TRPM7. (A) TRPM6 and TRPM7 contain both channel (blue) and alpha-kinase domains (KIN). The typical TRP domain is present directly COOH-terminal to the last transmembrane domain. Following the TRP domain is the coiled-coil domain (CC), which is assumed to be important to channel assembly [86]. Just before the alpha-kinase domain is a Ser/Thr-rich region (S/T) containing multiple autophosphorylation sites that are proposed to play a role in substrate recognition [12]. The cytoplasmic NH₂-terminus contains a region with high sequence similarity to melastatin (TRPM1), the founding member of the melastatin-related TRP (TRPM) family. The function of the TRPM (melastin-like TRP) region is not known with the exception that residues within this domain (87–326) interact with the synaptic protein snapin [62]. (B) Current-voltage relationship of whole-cell currents typically displayed by TRPM6 and TRPM7. Shown is a representative current-voltage relationship of whole-cell current obtained in HEK-293 cells expressing mouse TRPM7. TRPM6- and TRPM7-mediated currents are characterized by pronounced outward rectification with a small inward current in the presence of normal external concentrations of Ca²⁺ and Mg²⁺.