In vitro and in vivo characterization of a gain-of-function mutation of TRPM3 associated with peripheral disability and epilepsy

Chronic pain is a major health problem with an estimated 100 million people suffering from it in Europe. Despite the tremendous amount of analgesics, the majority of patients cannot be helped with the drugs currently on the market, reducing the quality of life significantly. New approaches are of high need and could be the start for new therapeutics. TRPM3 is a non-selective cation channel that can be activated by a plethora of stimuli. Evidence is provided that TRPM3 plays a role in heat-evoked pain responses. Remarkably, two de novo mutations in the human Trpm3-gene were very recently described causing intellectual disability and epilepsy. Seven out of eight patients were heterozygous for the V990M substitution and only one patient was heterozygous for the P1090Q substitution. Interestingly, some of these patients indicated to have an altered pain and heat threshold. This project aims to evaluate the effect of the V990M substitution in human TRPM3 in the central and the peripheral nervous system. To do so, we will provide a characterization of the V990M mutation in vitro and in vivo using electrophysiological and behavioral techniques. A better understanding on the impact of this mutation could bring new light to therapeutics targeting TRPM3 and validate TRPM3 as an important nociceptor in humans.