1.A.4.1.5
Transient receptor potential canonical-6, TRPC6,  a non-selective cation channel that is directly activated by diacylglycerol (DAG (Szabó et al. 2015). Mutation causes a particularly aggressive form of familial focal segmental glomerulosclerosis (Winn et al., 2005; Mukerji et al., 2007). Tang et al. 2018 presented the structure of the human TRPC6 homotetramer in complex with a high-affinity inhibitor, BTDM, solved by single-particle cryo-EM to 3.8 Å resolution. The structure shows a two-layer architecture in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domains, including the N-terminal ankyrin repeats and the C-terminal coiled-coil, contribute to the tetramer assembly. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening (Tang et al. 2018).  TRPC6 may regulate the glomerular filtration rate by modulating mesangial cell contractile function through multiple Ca²⁺ signaling pathways (Li et al. 2017). Several proteins including podocin (8.A.21.1.2), nephrin (8.A.23.1.33), CD2AP (8.A.34.1.5) and TRPC6 form a macromolecular assembly that constitutes the slit-diaphragm in podocytes that resembles tight junctions (Mulukala et al. 2020). Two small molecules, GSK1702934A and M085, directly activate TRPC6 via a mechanism involving stimulation of the extracellular cavity formed by the pore helix and transmembrane helix S6 (Yang et al. 2021). Na⁺/Ca²⁺ exchanger, NCX1, and canonical transient receptor potential channel 6 (TRPC6) are recruited by STIM1 to mediate Store-Operated Calcium Entry in primary cortical neurons (Tedeschi et al. 2022). 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). The selective TRPC6 agonist, 3-(3-,4-Dihydro-6,7-dimethoxy-3,3-dimethyl-1-isoquinolinyl)-2H-1-benzopyran-2-one (C20) binds to the extracellular agonist binding site of  TRPC6, protects hippocampal mushroom spines from amyloid toxicity in vitro, efficiently recovers synaptic plasticity in 5xFAD brain slices, penetrates the blood-brain barrier and recovers cognitive deficits in 5xFAD mice. Thus, C20 is the novel TRPC6-selective drug suitable to treat synaptic deficiency in Alzheimer's disease-affected hippocampal neurons (Zernov et al. 2022). Paraoxonase 2 (PON2) deficiency reproduces lipid alterations of diabetic and inflammatory glomerular disease while affecting TRPC6 signaling (Hagmann et al. 2022). Capsazepine (CPZ) inhibits TRPC6 conductance and is protective in adriamycin-induced nephropathy and diabetic glomerulopathy (Hagmann et al. 2023). The mammalian TRPC subfamily comprises seven transmembrane proteins (TRPC1-7) forming cation channels in the plasma membrane of mammalian cells. TRPC channels mediate Ca²⁺ and Na⁺ influx into cells. Amongst TRPCs, TRPC6 deficiency or increased activity due to gain-of-function mutations has been associated with multiple diseases, such as kidney, pulmonary, and neurological diseases. Indeed, the TRPC6 protein is expressed in various organs and is involved in diverse signalling pathways. The last decade saw a surge in studies concerning the physiological roles of TRPC6 and describing the development of new pharmacological tools modulating TRPC6 activity (Saqib et al. 2023). One defective TRPC6 gene copy is not sufficient to cause focal segmental glomerulosclerosis (FSGS), which is inherited as an autosomal dominant disease. Increased rather than reduced calcium influx through TRPC6 is required for podocyte cell death (Batool et al. 2023). Pharmacological activation of the TRPC6 channel prevents colitis progression (Nishiyama et al. 2024). Steroid-resistant nephrotic syndrome is due to variants of the TRPC6 gene (Zhao et al. 2024).  The discovery of TRPC6 in glandular tissues indicates a role in salivary gland function and calcium homeostasis (Carl et al. 2024).