High resolution cryo-EM structures of TRPC5-Gαi3 complexes reveal direct activation of an ion channel by Gαi-GTP.

Transient receptor potential canonical 4 and 5 (TRPC4 and TRPC5) are Ca2+-permeable nonselective cation channels known to be activated by Gi/o proteins. Recently, Won et al. (Nat Commun. 2023, 14:2550) reported the cryo-EM structures of TRPC5 in complex with Gαi3. The G protein alpha subunit was found to directly bind to an ankyrin-like repeat domain in the periphery of the cytosolic portion of TRPC5 some 50 Å away from the membrane. This establishes the TRPC4/C5 ion channels as true effectors of Gα subunits, although the channel gating still depends on the coexistence of Ca2+ and phosphatidylinositol 4,5-bisphosphate.