Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

Abstract

Canonical or classical transient receptor potential 4 and 5 proteins (TRPC4 and TRPC5) assemble as homomers or heteromerize with TRPC1 protein to form functional nonselective cationic channels with high calcium permeability. These channel complexes, TRPC1/4/5, are widely expressed in nervous and cardiovascular systems, also in other human tissues and cell types. It is debatable that TRPC1 protein is able to form a functional ion channel on its own. A recent explosion of molecular information about TRPC1/4/5 has emerged including knowledge of their distribution, function, and regulation suggesting these three members of the TRPC subfamily of TRP channels play crucial roles in human physiology and pathology. Therefore, these ion channels represent potential drug targets for cancer, epilepsy, anxiety, pain, and cardiac remodelling. In recent years, a number of highly selective small-molecule modulators of TRPC1/4/5 channels have been identified as being potent with improved pharmacological properties. This review will focus on recent remarkable small-molecule agonists: (-)-englerin A and tonantzitlolone and antagonists: Pico145 and HC7090, of TPRC1/4/5 channels. In addition, this work highlights other recently identified modulators of these channels such as the benzothiadiazine derivative, riluzole, ML204, clemizole, and AC1903. Together, these treasure troves of agonists and antagonists of TRPC1/4/5 channels provide valuable hints to comprehend the functional importance of these ion channels in native cells and in vivo animal models. Importantly, human diseases and disorders mediated by these proteins can be studied using these compounds to perhaps initiate drug discovery efforts to develop novel therapeutic agents.

Figure 1

Proposed membrane topology structure of the TRPC1/4/5 channels. (a) The suggested structure topology of monomeric TRPC1/4/5 channels consist of six membrane‐spanning domains, S1–S6, interconnected by short loops and the putative pore region loop between transmembrane segments S5 and S6 enabling entry of cations primarily Ca²⁺. The amino (N) and carboxyl (C) termini are located intracellularly and mediate downstream signalling. (b) Schematic structure of functional tetrameric assembly for a monomeric or a heteromeric complex of TRPC1/4/5. The recent novel and most potent agonists and antagonists are shown in (b)

Figure 2

The putative roles of TRPC1/4/5 channels in human health and diseases

Figure 3

The chemical structures of EA inactive metabolite, (−)‐englerin B, and the EA analogue, 54, which antagonizes EA at TRPC1/4/5 channels