Structural mechanism of TRPM7 channel regulation by intracellular magnesium

Zn(2+), Mg(2+) and Ca(2+) are essential divalent cations implicated in many metabolic processes and signalling pathways. An emerging new paradigm is that the organismal balance of these cations predominantly depends on a common gatekeeper, the channel-kinase TRPM7. Despite extensive electrophysiological studies and recent cryo-EM analysis, an open question is how the channel activity of TRPM7 is activated. Here, we performed site-directed mutagenesis of mouse TRPM7 in conjunction with patch-clamp assessment of whole-cell and single-channel activity and molecular dynamics (MD) simulations to show that the side chains of conserved N1097 form an inter-subunit Mg(2+) regulatory site located in the lower channel gate of TRPM7. Our results suggest that intracellular Mg(2+) binds to this site and stabilizes the TRPM7 channel in the closed state, whereas the removal of Mg(2+) favours the opening of TRPM7. Hence, our study identifies the structural underpinnings through which the TRPM7 channel is controlled by cytosolic Mg(2+), representing a new structure–function relationship not yet explored among TRPM channels. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04192-7.