Molecular architecture of the human TRPC1/C5 heteromeric channel

Transient receptor potential (TRP) ion channels form heteromers through combinatorial associations of distinct subunits, contributing to the diversity of TRP channel functions. Among them, TRPC5, which forms a heteromer with TRPC1, represents an attractive pharmaceutical target for treating anxiety and depression. Here, we present the cryo-electron microscopy structure of the human TRPC1/C5 heteromer, composed of one TRPC1 subunit and three TRPC5 subunits. The incorporation of TRPC1 into the heteromer disrupts the C4 symmetry of the TRPC5 homotetramer, resulting in a distinct ion conduction pathway characterized by an asymmetrically constricted selectivity filter and an asymmetric lower gate. The TRPC1/C5 heteromer displays recognizable structural features compared to the TRPC1/C4 heteromer, including a noncanonically tilted coiled-coil domain and a distinct intersubunit interactions. Furthermore, we elucidate the structures of human TRPC5 bound to the TRPC1/4/5-specific agonist, (−)-Englerin A. Our findings establish a foundation for exploring the diversity of heteromeric TRP channels and pave the way for targeting TRPC1/C5 as a therapeutic strategy. TRPC5 ion channels play a critical role in the brain. Here, the authors report cryo-EM structures of the TRPC1/C5 heteromer and TRPC5 bound to two agonists, providing structural insights into channel assembly and modulation.