The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7

Abstract

TRPM7 is a member of the melastatin-related subfamily of TRP channels and represents a protein that contains both an ion channel and a kinase domain. The protein is ubiquitously expressed and represents the only ion channel known that is essential for cellular viability. TRPM7 is a divalent cation-selective ion channel that is permeable to Ca2+ and Mg2+, but also conducts essential metals such as Zn2+, Mn2+, and Co2+, as well as nonphysiologic or toxic metals such as Ni2+, Cd2+, Ba2+, and Sr2+. The channel is constitutively open but strongly downregulated by intracellular levels of Mg2+ and MgATP and other Mg-nucleotides. Reducing the cellular levels of these regulators leads to activation of TRPM7-mediated currents that exhibit a characteristic nonlinear current-voltage relationship with pronounced outward rectification due to divalent influx at physiologically negative voltages and monovalent outward fluxes at positive voltages. TRPM7 channel activity is also actively regulated following receptor-mediated changes in cyclic AMP (cAMP) and protein kinase A activity. This regulation as well as that by Mg-nucleotides requires a functional endogenous kinase domain. The function of the kinase domain is not completely understood, but may involve autophosphorylation of TRPM7 as well as phosphorylation of other target proteins such as annexin and myosin IIA heavy chain. Based on these properties, TRPM7 is currently believed to represent a ubiquitous homeostatic mechanism that regulates Ca2+ and Mg2+ fluxes based on the metabolic state of the cell. Physiologically, the channel may serve as a regulated transport mechanism for these ions that could affect cell adhesion, cell growth and proliferation, and even cell death under pathological stress such as anoxia.

Fig. 1

a–d Development of heterologous and endogenous TRPM7 currents. a Representative development of heterologous TRPM7 currents in overexpressing HEK-293 cells where free Mg²⁺]_i was kept at 800 μM and MgATP was omitted (n = 6). Data points correspond to average and normalized current amplitudes measured at −80 mV (closed circles) and +80 mV (open circles) and plotted as a function of time. Note that TRPM7 develops immediately. b Current–voltage (I–V) relationship of heterologous TRPM7 extracted from an example cell at 200 s. c Representative development of endogenous TRPM7-like MagNuM currents measured in RBL-2H3 cells. Average inward (closed circles) and outward (open circles) currents at −80 mV and +80 mV, respectively (n = 6), recorded under conditions that suppress I_CRAC and support MagNuM activation (omission of MgATP, free [Mg2+]_i = 760 μM, free [Ca²⁺]_i = 100 nM). Note that MagNuM starts to develop around 80 s into the experiment. d Representative I–V relationship of endogenous TRPM7-like MagNuM extracted at 300 s after whole-cell establishment