BPS2026 – Molecular mechanisms of TRPM1 regulation by heterotrimeric G-protein

TRPM1, an ion channel highly expressed in ON-bipolar cells in the retina, plays an important role in transmitting the vision signal in low-light environments. Electrophysiological studies on TRPM1 have shown its inhibition by the activation of mGluR6, a G-protein coupled receptor (GPCR) which responds to the neurotransmitter glutamate. It has been hypothesized that the Gα and Gβγ released upon mGluR6 activation inhibits TRPM1. However, much debate remains on how exactly TRPM1 is inhibited, with some studies indicating an inhibition by only Gα and not Gβγ, and others indicating the opposite. We aim to determine the precise G protein partner of TRPM1 through a combination of structural and functional analyses. The results of our work could not only provide insights into the molecular mechanism underlying GPCR regulation of TRPM1 and other related transient receptor potential (TRP) channels but also facilitate the development of novel therapeutics treating TRPM1-associated vision disorders.