A duo of redox-sensitive pore-loop cysteines controls the activity of the neural ion channel TRPM3
Year: 2026
Type: article
Abstract: 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.
Source: Communications Chemistry
Institutions: VIB-KU Leuven Center for Brain & Disease Research, KU Leuven
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,690
Awards: TRPM3 - a key regulator of inflammatory pain, Multidisciplinary Training of Young Researchers in Novel Implantable Bio-inspired sensors, In vitro and in vivo characterization of a gain-of-function mutation of TRPM3 associated with peripheral disability and epilepsy, G434337789, The role of TRPM3 in the development of pathological pain - from the periphery to the brain, Regulation of the nociceptor TRPM3 by reactive oxygen species and the implications on pain conditions., G595479184, Investigating TRPM3 as a nociceptor for endometriosis-associated pain, An integrated approach to monitor the development and treatment of chronic pain., G8276607783, G8452356291, Molecular basis and physiological relevance of an alternative ion permeation pathway in TRPM3 channels.
OpenAlex ID: W7123397027