TRPM7 kinase activity regulates murine mast cell degranulation

Abstract

Transient receptor potential melastatin 7 (TRPM7) is a divalent ion channel with a C-terminally located α-kinase. Heterozygous mice for a TRPM7 kinase deletion (TRPM7^+/∆K) are hypomagnesemic and hyperallergic. In contrast, mice carrying a single point mutation at amino acid 1648, which silences TRPM7 kinase activity (TRPM7^KR), are not hyperallergic and are resistant to systemic magnesium (Mg²⁺) deprivation. Since allergic reactions are triggered by mast cell-mediated histamine release, we investigated the function of TRPM7 on mast cell degranulation and histamine release using wild type (TRPM7^+/+), TRPM7^+/∆K and TRPM7^KR mice. We found that degranulation and histamine release proceeded independently of TRPM7 channel function. Furthermore, extracellular Mg²⁺ ([Mg2+]_e) assured unperturbed IgE-DNP-dependent exocytosis, independently of TRPM7. However, impairment of TRPM7 kinase function suppressed IgE-DNP-dependent exocytosis, slowed the cellular degranulation rate, and diminished the sensitivity to intracellular calcium [Ca²⁺]_i in G protein-induced exocytosis. In addition, G protein-coupled receptor (GPCR) stimulation revealed strong suppression of histamine release, whereas removal of [Mg2+]_e reverted this phenotype. We conclude that the TRPM7 kinase activity regulates murine mast cell degranulation by changing its sensitivity to [Ca²⁺]_i and affecting granular mobility and/or histamine contents.

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