TRPC Channels

TRP canonical (TRPC) channels are the most closely related to the prototypical Drosophila TRP, the loss of which leads to the transient receptor potential (TRP) phenotype in the fruit fly. Despite the name, mammalian TRPCs are not involved in vision. Instead, these Ca²⁺-permeable nonselective cation channels contribute to store- and receptor-operated Ca²⁺ entry and membrane potential depolarization downstream from phospholipase C pathways following ligand stimulation of G protein-coupled receptors and receptor tyrosine kinases. While all TRPCs can be directly activated by diacylglycerols, TRPC4/C5 also respond to G_i/o proteins. Phosphatidylinositol 4,5-bisphosphate, Ca², and H⁺ also contribute to channel activation. The presence of multiple factors that affect the relative response levels of TRPC channels suggests that these channels may serve as coincidence detectors of signaling by divergent inputs, through which they fine-tune the outputs of targeting cells. Recent high-resolution cryo-EM structures of ligand-free and ligand-bound TRPC channels have unveiled great details on TRPC channel assembly and structural organization, as well as the key regulatory sites for gating and ligand interaction. The improvement in TRPC pharmacology and genetic approaches are enriching the current knowledge on the physiological functions of TRPC channels and their contributions to disease.