Structural mechanism of TRPC3 inhibition by a potent and selective antagonist

Abstract The transient receptor channel canonical family member 3 (TRPC3) is a non-selective, calcium-permeable cation channel within the larger TRP superfamily. TRPC3 is expressed in both excitable and non-excitable cells, where it integrates multiple signaling pathways and is directly activated by binding of diacylglycerol following activation of G-protein coupled receptors. Increased TRPC3 signaling is implicated in several diseases, highlighting TRPC3 as a potential therapeutic target. However, the development of TRPC3 inhibitors with suitable potency and selectivity has been challenging due to the channel’s high structural and sequence homology with related family members, particularly TRPC6. Here, we present a novel, selective and highly potent TRPC3 antagonist (GSK2820986A) featuring an anilino-thiazole pharmacophore. Through a combination of molecular dynamic simulations and functional assays, we identify a putative binding site for GSK2820986A in the S4-S5 pocket and propose a potential inhibitory mechanism. Our findings provide a powerful tool compound and mechanistic framework to advance the investigation and therapeutic targeting of TRPC3 in disease.