Structural biology of the TRPM4 channel: architecture, modulation, and therapeutic opportunities.

TRPM4 is a Ca2+-activated, monovalent-selective cation channel that conducts Na+ and K+ while remaining essentially impermeable to Ca2+. By translating cytosolic Ca2+ elevations into membrane depolarization rather than additional Ca2+ influx, TRPM4 operates as an electrical signal converter that tunes excitability, secretion, vascular tone, immune-cell behavior, and cell-death pathways. Dysregulated TRPM4 activity has been implicated in cardiac conduction disease, acute central nervous system injury and edema, and several cancers, making the channel a clinically relevant but mechanistically demanding target. Recent cryo-electron microscopy (cryo-EM) structures have transformed the field by resolving TRPM4 in closed, non-conductive intermediate, pre-open, open-pore, and drug-bound conformations, and by defining the allosteric interfaces that connect Ca2+ sensing, phosphoinositide binding, nucleotide inhibition, temperature-dependent remodeling, and pore opening. In parallel, pharmacology has advanced from low-selectivity tool compounds toward structurally localized inhibitors, direct agonists, extracellular antibodies, and prospective engineered binders whose mechanisms can be interpreted in state-dependent terms. Here, we synthesize this structural and pharmacological evidence to explain how TRPM4 architecture encodes modulation and gating, and how disease context should guide therapeutic strategy. We argue that the central challenge is no longer simply to activate or inhibit TRPM4, but to stabilize the right conformational state in the right tissue at the right stage of pathology. Finally, we discuss nanobodies as promising state-selective tools and potential biologics for next-generation TRPM4 modulation.