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Review
. 2018 Jun 1;7(6):52.
doi: 10.3390/cells7060052.

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

Aisling Minard  1 , Claudia C Bauer  2 , David J Wright  3 , Hussein N Rubaiy  4 , Katsuhiko Muraki  5 , David J Beech  6 , Robin S Bon  7
Affiliations
Review

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

Aisling Minard et al. Cells. .

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.

Keywords: TRPC; calcium; chemical probes; ion channel; small molecules.

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Conflict of interest statement

The authors declare no conflict of interest. A.M.’s PhD project is co-funded by AstraZeneca. The funders had no role in the design or preparation of this review, nor in the decision to publish it.

Figures

Figure 1
Figure 1
(A) Formation of tetrameric TRPC1/4/5 cation channels by TRPC1/4/5 proteins and recently discovered small-molecule modulators discussed in this review. Domains “A” are the ankyrin repeat domains present in all TRPC proteins, and “P” is the PDZ binding domain present in TRPC4 and TRPC5. (B) Composition of different TRPC1/4/5 channels discussed in this review. Native channels are believed to exist predominantly as heteromers, but their exact compositions and stoichiometries are often unknown (as depicted by white subunits, which may be TRPC1/4/5 proteins or other TRP(C) proteins). Linked subunits depict recombinant TRPC4–C1 and TRPC5–C1 concatemeric proteins that can be used to control channel stoichiometry.
Figure 2
Figure 2
Example I–V plots of homomeric (left) and heteromeric/concatemeric (right) TRPC1/4/5 channels. Recordings from overexpressed TRPC4:C4 and TRPC1:C4 channels are shown. For examples of native I–V plots, see references [14,16].
Figure 3
Figure 3
Structures of recently reported TRPC1/4/5 activators, the (−)EA metabolite (−)EB, and the (−)EA antagonist A54.
Figure 4
Figure 4
Structures of ML204 and recently reported TRPC1/4/5 inhibitors.
See this image and copyright information in PMC

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