BPS2026 – TRPM3—From the periphery to the brain

The transient receptor potential (TRP) channel TRPM3 is a calcium-permeable cation channel activated by heat and by the neurosteroid pregnenolone sulfate (PregS). TRPM3 is highly expressed in sensory neurons, where it plays a key role noxious heat sensing. Upregulation of TRPM3 expression and function contributes to hypersensitivity and ongoing pain in a variety of pain models, and genetic elimination of TRPM3 reduces evoked and ongoing pain in these models. We have developed potent, peripherally restricted TRPM3 antagonists, the first of which are currently being tested in Phase 2 clinical trials. Recently, de novo TRPM3 variants were described in patients with neurodevelopmental delay, intellectual disability and epilepsy. These variants lead to a dominant gain of channel function, including increased sensitivity to heat and neurosteroid. These findings indicate an important role for TRPM3 in brain development and function, and suggest that TRPM3 antagonists may be developed as a possible therapy for brain diseases.