TRPM6 and TRPM7: A Mul-TRP-PLIK-Cation of Channel Functions

Loren      W. Runnels

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.

Keywords: TRPM6, channel, kinase, calcium, magnesium, TRPM7, Mul-TRP-PLIK-Cation, magnesium homeostasis, skeletogenesis, melanopore formation, thymopoiesis, cell adhesion, hypomagnesemia, hypocalcemia, melanoma kinase, protein kinases, TRP-PLIK, LTRPC7, CHAK1, transient receptor potential, kidney kinase, COOH-terminal tails, Dictyostelium myosin II heavy chain kinases, elongation factor 2 kinase, phosphorylation, alpha-kinases, PKA, autophosphorylation, dimerization sequence, Xenopus oocytes, CHO-K1 cells, TRPM6 cDNA, non-selective channel blocker 2-APB, GXGXXG, CHO-K1, pyrimidine-based nucleoside triphosphates, TRPM7--kinase, Gly1799, Demeuse's measurements, phospholipase C-1 (PLC1), cAMP, 17--estradiol, DT40-KO, KMG104AM, small interfering RNA, TGF-1,, bradykinin-stimulated Ca2+, myosin IIA