1.A.4.1.4
TRPC3 store-operated non-selective cation channel (activated by thapsigargin and 2 acyl glycerol; forms a heteromeric channel with TrpC1, TC #1.A.4.1.3) (Liu et al., 2005).  A  structural model of the TRPC3 permeation pathway based on a sodium channel (TC# 1.A.1.14.5) with a localized selectivity filter and an occluding gate with evidence for allosteric coupling between the gate and the selectivity filter has been proposed (Ko et al. 2009; Lichtenegger et al. 2013). The channel may have a large internal chamber surrounded by signal sensing antennas (Mio et al. 2007). TRPC channels are involved in store-operated calcium entry and calcium homeostasis, and they are implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia (Fan et al. 2018). The structure in a lipid-occupied, closed state has been solved at 3.3 Å resolution. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to, and thus disengaged from, the pore-lining S6, suggesting a different gating mechanism from other TRP subfamily channels. The third transmembrane helix S3 is remarkably long, shaping a unique transmembrane domain, and constituting an extracellular domain that may serve as a sensor of external stimuli. Fan et al. 2018 identified two lipid binding sites, one being sandwiched between the pre-S1 elbow and the S4-S5 linker, and the other being close to the ion-conducting pore, where the conserved LWF motif of the TRPC family is located. The cytoplasmic domain allosterically modulates channel gating (Sierra-Valdez et al. 2018). This channel may be present in mitochondria (Parrasia et al. 2019). TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal segmental glomerulosclerosis (FSGS) in humans. Guo et al. 2022 reported the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. They identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. These calcium sensors are structurally and functionally conserved in TRPC6. The GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. Structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets revealed different conformations of the transmembrane domain (Guo et al. 2022). TRPC3 is primarily gated by lipids, and its surface expression is dependent on cholesterol (Clarke et al. 2022). Regulating the activity of the SOCE response via SARAF activity may allow therapeutic strategies for triple-negative breast cancer (Saldías et al. 2023).