A duo of redox-sensitive pore-loop cysteines controls the activity of the neural ion channel TRPM3

Transient Receptor Potential Melastatin 3 (TRPM3) is a non-selective, Ca ²⁺ -permeable ion channel that plays a pivotal role in peripheral thermosensation and nociception. Moreover, gain-of-function variants in TRPM3 underlie a spectrum of neurodevelopmental and epileptic disorders in humans, indicating an important role of TRPM3 in the central nervous system. Oxidative stress contributes to various neurological disorders of both the central and peripheral nervous system, but it is unknown whether TRPM3 activity is altered by the cellular redox state. Here, we report a direct, bidirectional modification of TRPM3 channel activity by oxidizing and reducing agents. Our data, obtained both in a heterologous expression system and in mouse sensory neurons and pancreatic islet cells, demonstrate a profound effect of the redox state on the channel properties of TRPM3, including a robust shift in the response profile to TRPM3 agonists and antagonists and in the modulation by G protein-coupled receptors. In addition, we identified two cysteine residues in the extracellular pore loop of TRPM3 that underlie the redox-control of the channel, due to the reversible formation of intra-subunit cysteine bridges. Taken together, these findings establish a novel mechanism of TRPM3 channel modulation, with potentially important ramifications for pain signaling and neurological disorders.