TRPC3 as a Target of Novel Therapeutic Interventions

Abstract

TRPC3 is one of the classical members of the mammalian transient receptor potential (TRP) superfamily of ion channels. TRPC3 is a molecule with intriguing sensory features including the direct recognition of and activation by diacylglycerols (DAG). Although TRPC3 channels are ubiquitously expressed, they appear to control functions of the cardiovascular system and the brain in a highly specific manner. Moreover, a role of TRPC3 in immunity, cancer, and tissue remodeling has been proposed, generating much interest in TRPC3 as a target for pharmacological intervention. Advances in the understanding of molecular architecture and structure-function relations of TRPC3 have been the foundations for novel therapeutic approaches, such as photopharmacology and optochemical genetics of TRPC3. This review provides an account of advances in therapeutic targeting of TRPC3 channels.

Keywords: TRPC3 pharmacology; channel structure; lipid mediators; photochromic ligands; transient receptor potential channels.

Figure 1

Chemical structures of prototypical antagonist and agonists of transient receptor potential channel 3/6 (TRPC3/6): Pyrazole 3 (Pyr3) as a most commonly used pore blocker; GSK1702934A and 2-Acetyl-1-oleoyl-sn-glycerol (OAG) represent channel agonists (a synthetic, non-lipid activator, and a diacylglycerol/lipid, respectively); OptoDArG as a photochromic agonist (photoswitchable lipid) and a powerful tool for precise control of TRP channels (TRPC) activity.

Figure 2

Ligand-channel interactions and potential drug binding sites in TRPC3. (a) Schematic illustration of the domain structure of one TRPC3 channel subunit according to information provided in Fan et al. [7]. Lipid binding sites (green stars) are indicated with L1 (formed by LD9, pre-S1, S1, S4, and S4–S5 linker) and L2 (between p-loop and S6 helix); potential modulator binding site (M) represented by a cavity (extracellular domain) formed by the extended S3 helix, S1–S2 and S3–S4 linkers as previously identified [7]. Proposed BTDM binding site formed by S3, S4–S5 linker, S4, S5, and S6 identified by Tang et al. [8]. (b) Detailed view on postulated 2-(benzo[d][1,3]dioxol-5-ylamino)thiazol-4-yl) ((3S,5R)-3,5-dimethylpiperidin-1-yl)methanone (BTDM) binding site in TRPC3: amino acids in the TRPC3 sequence, corresponding to the TRPC6 BTDM binding site are marked in red. The BTDM molecule is only schematically introduced into the TRPC structure and not adjusted in size. The glycine residue G652 (here G640, isoform 1/Q13507-1 in UniProt) identified as crucial for recognition and accommodation of lipid activators is highlighted in blue [14]. The BTDM molecule is schematically placed into the proposed binding site.