マウスにおけるTRPM7キナーゼのα細胞増殖およびグルカゴン産生制御

Glucagon is essential for maintaining glucose homeostasis, yet the molecular mechanisms governing α-cell function remain incompletely understood. Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed ion channel with an intrinsic kinase domain, which regulates the mammalian target of rapamycin (mTOR) signaling in various cell types. Given the central role of mTOR in α-cell regulation, this study investigates how TRPM7 influences α-cell biology and examines whether its function is modulated through interaction with the mTOR signaling pathway.

Islets were isolated from wild-type (WT) mice and mice lacking TRPM7 kinase activity (Trpm7^R/R). Functional analyses included Bio-Plex assays, RNA sequencing, glucagon ELISA, qRT-PCR, Western blotting, immunocytochemistry, and patch-clamp recordings. αTC1c9 cells were used as a murine α-cell model. NS8593, a small synthetic compound, was used as a potent TRPM7 inhibitor.

Ex vivo analysis revealed impaired mTOR signaling in Trpm7^R/R islets. Trpm7^R/R islets secreted less glucagon in response to various secretagogues compared to WT controls. This reduction was partially caused by diminished glucagon content due to downregulation of key transcriptional regulators of glucagon biosynthesis, including Gcg and Mafb. Morphological analysis identified reduced proliferation and enhanced apoptosis of Trpm7^R/R α-cells. Similarly, pharmacological inhibition of TRPM7 impaired mTOR signaling, suppressed α -cell identity, and α-cell proliferation in both WT islets and αTC1c9 cells.

Loss of TRPM7 kinase function impairs mTOR signaling, leading to reduced α-cell proliferation and glucagon secretion. Our findings show that the TRPM7 kinase/mTOR signaling pathway axis is a critical regulator of α-cell function in mice.