Remarkable Progress with Small-Molecule Modulation of TRPC1/4/5 Channels: Implications for Understanding the Channels in Health and Disease

Abstract

Proteins of the TRPC family can form many homo- and heterotetrameric cation channels permeable to Na+, K+ and Ca2+. In this review, we focus on channels formed by the isoforms TRPC1, TRPC4 and TRPC5. We review evidence for the formation of different TRPC1/4/5 tetramers, give an overview of recently developed small-molecule TRPC1/4/5 activators and inhibitors, highlight examples of biological roles of TRPC1/4/5 channels in different tissues and pathologies, and discuss how high-quality chemical probes of TRPC1/4/5 modulators can be used to understand the involvement of TRPC1/4/5 channels in physiological and pathophysiological processes.

Cryo-EM structures of human TRPC5 reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site

“…10 TRPC1 (48% and 47% sequence identity to TRPC4 and TRPC5, respectively) is not thought to form functional homomeric channels, but is widely expressed and an important contributor to heteromeric TRPC1/4/5 ion channels. [10][11][12][13][14][15] Although disruption of the Trpc4/5 genes 16 and global expression of a dominant-negative mutant TRPC5 12 do not cause catastrophic phenotypes in rodents, TRPC1/4/5 channels have been implicated in a wide range of physiological and pathological mechanisms. 4,5,10,17 These findings have driven the development of potent and selective TRPC1/4/5 modulators as chemical probes and drug candidates, 5,10,18 and clinical trials have been started by Hydra Biosciences/Boehringer Ingelheim (the TRPC4/5 channel inhibitor BI 135889 for treatment of anxiety/CNS disorders) and Goldfinch Bio (the TRPC5 channel inhibitor GFB-887 for genetically-driven kidney disease).…”

“…Physiological activation and modulation of TRPC1/4/5 channel activity is complex, [4][5][6] and may include mediation by endogenous and dietary lipids. 12,[19][20][21][22] In addition, structurally diverse pharmacological modulators have been reported, 5,10,18 including inhibitors suitable for studies of TRPC1/4/5 in cells, tissues and animal models such as the xanthines Pico145 (also called HC-608) [23][24][25] and HC-070, 24,25 the pyridazinone derivative GFB-8438, 26 and the benzimidazole ML204. 27 However, structural insight into the mode-of-action of small-molecule TRPC1/4/5 modulators is lacking, and no small-molecule binding sites have been identified.…”

Potent, selective, and subunit‐dependent activation of TRPC5 channels by a xanthine derivative

“…Cryo-EM structures of mouse TRPC4:C4 (Duan et al, 2018), zebrafish TRPC4:C4 (Vinayagam et al, 2018), and mouse TRPC5:C5 (Duan et al, 2019) have recently been reported. However, the precise native stoichiometries of TRPC1/4/5 channels are largely unknown (Minard et al, 2018). Overexpression of TRPC4 or TRPC5 protein leads to functional homotetramers, whereas the TRPC1 protein may not form functional homomeric channels but is widely expressed and an important contributor to heteromeric channels, for example, with TRPC4 and/or TRPC5 (Akbulut et al, 2015;Bon & Beech, 2013;Bröker-Lai et al, 2017;Dietrich, Fahlbusch, & Gudermann, 2014;Ludlow et al, 2017;Minard et al, 2018;Sukumar et al, 2012).…”

“…Although observational clinical studies and changes detected in genetically or pharmacologically modified rodents and/or human tissue suggest multiple physiological roles of TRPC1/4/5 channels (Bon & Beech, 2013;Bröker-Lai et al, 2017;Lau et al, 2016;Lepannetier et al, 2018), disruption of the Trpc4/5 genes (Suresh Babu, Wojtowicz, Birnbaumer, Hecker, & Cattaruzza, 2012) and global expression of a dominant-negative mutant TRPC5 (Sukumar et al, 2012) do not cause catastrophic phenotypes. However, the involvement of TRPC1/4/5 channels in various human diseases-including CNS disorders, kidney disease, cancer, cardiovascular disease, and complications of diabetes -has led these channels to emerge as potential therapeutic targets (Bon & Beech, 2013;Gaunt, Vasudev, & Beech, 2016;Just et al, 2018;Minard et al, 2018;Zhou et al, 2017).…”

“…Several highly potent and selective TRPC1/4/5 modulators have been described recently (Minard et al, 2018). Currently, the most potent TRPC1/4/5 activator is the natural product (−)-englerin A (EA; Akbulut et al, 2015;Carson et al, 2015;Ludlow et al, 2017;Muraki et al, 2017), which induces strong TRPC1/4/5 currents at nanomolar concentrations.…”