Structural landscape of activation, desensitization and inhibition in the human TRPM4 channel

Abstract TRPM4 is a member of the transient receptor potential melastatin channel subfamily and functions as a Ca 2+ -activated monovalent-selective cation channel. It is widely expressed in various cells and tissues, where its activation depolarizes the plasma membrane potential and modulates various Ca 2+ -dependent biological processes. TRPM4 activity is potentiated by membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) and inhibited by cytosolic free adenosine triphosphate (ATP), allowing the channel to transition between different functional states in response to dynamic changes in cellular Ca 2+ , ATP and PtdIns(4,5)P 2 levels during signaling events. Here we present single-particle cryo-electron microscopy structures of human TRPM4 in four distinct states: apo closed, Ca 2+ -bound putative desensitized, Ca 2+ -PtdIns(4,5)P 2 -bound open and ATP-bound inhibited. Combined with mutagenesis and electrophysiological analyses, these structures reveal the molecular mechanisms underlying TRPM4 activation, desensitization and inhibition. Given the central roles of Ca 2+ , PtdIns(4,5)P 2 and ATP in cellular signaling, this work provides a structural foundation to decipher the physiological functions of TRPM4 across diverse biological systems.