Redox reagents as important modulators of the TRPM3 channel activity

The transient receptor potential Melastatin 3 (TRPM3), one of the major transduction channels in the pain pathway, integrates information from extracellular milieu to control excitability of primary nociceptive neurons. Sensitization of TRPM3 heightens pain sensation to moderately noxious or even innocuous stimuli. We report here that oxidative stress markedly modulate TRPM3 activity and responsivity to pregnenolone sulphate stimulation. The sensitization can be recapitulated in endogenous expression systems like neurons of the somatosensory system. Moreover, our preliminary results identified a cysteine required for full modulation of TRPM3 by oxidative challenges. Thus, oxidative modulation is a robust mechanism tuning TRPM3 activity via covalent modification of cysteines and may play a role in pain sensing processes during inflammation, infection, or tissue injury. In this project we aim to further investigate the modulation of TRPM3 activity by oxidative challenges by in vitro and in vivo research protocols. The outcome is of project is expected to identify TRPM3 as an important modulator to induce pain sensation during inflammation or tissue injury that can be modulated by reactive oxigen species. Moreover, it will provide further evidence for TRPM3 as a prominent target for the development of novel analgesics.