Inactivation of TRPM7 kinase activity does not impair its channel function in mice.

Abstract

Transient receptor potential (TRP) family channels are involved in sensory pathways and respond to various environmental stimuli. Among the members of this family, TRPM7 is a unique fusion of an ion channel and a C-terminus kinase domain that is highly expressed in immune cells. TRPM7 serves as a key molecule governing cellular Mg2+ homeostasis in mammals since its channel pore is permeable to Mg2+ ions and can act as a Mg2+ influx pathway. However, mechanistic links between its kinase activity and channel function have remained uncertain. In this study, we generated kinase inactive knock-in mutant mice by mutagenesis of a key lysine residue involved in Mg2+-ATP binding. These mutant mice were normal in development and general locomotor activity. In peritoneal macrophages isolated from adult animals the basal activity of TRPM7 channels prior to cytoplasmic Mg2+ depletion was significantly potentiated, while maximal current densities measured after Mg2+ depletion were unchanged in the absence of detectable kinase function. Serum total Ca2+ and Mg2+ levels were not significantly altered in kinase-inactive mutant mice. Our findings suggest that abolishing TRPM7 kinase activity does not impair its channel activity and kinase activity is not essential for regulation of mammalian Mg2+ homeostasis.