The newest TRP channelopathy: Gain of function TRPM3 mutations cause epilepsy and intellectual disability

Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca2+ permeable nonselective cation channel, activated by heat and chemical agonists, such as the endogenous neuro-steroid Pregnenolone Sulfate (PregS) and the chemical compound CIM0216. TRPM3 is expressed in peripheral sensory neurons of the dorsal root ganglia (DRG), and its role in noxious heat sensation in mice is well established. TRPM3 is also expressed in a number of other tissues, including the brain, but its role there has been largely unexplored. Recent reports showed that two mutations in TRPM3 are associated with a developmental and epileptic encephalopathy, pointing to an important role of TRPM3 in the human brain. Subsequent reports found that the two disease-associated mutations increased basal channel activity, and sensitivity of the channel to activation by heat and chemical agonists. This review will discuss these mutations in the context of human diseases caused by mutations in other TRP channels, and in the context of the biophysical properties and physiological functions of TRPM3.

Automated summary

TRPM3 is a Ca2+ permeable nonselective cation channel activated by heat and chemical agonists. It plays a critical role in noxious heat sensation in mice, while its role in the human brain remains largely unexplored. Mutations in TRPM3 have been associated with developmental and epileptic encephalopathy, indicating its important role in the human brain.