Pharmacology of TRPC Channels and Its Potential in Cardiovascular and Metabolic Medicine

Abstract

Transient receptor potential canonical (TRPC) proteins assemble to form homo- or heterotetrameric, nonselective cation channels permeable to K+, Na+, and Ca2+. TRPC channels are thought to act as complex integrators of physical and chemical environmental stimuli. Although the understanding of essential physiological roles of TRPC channels is incomplete, their implication in various pathological mechanisms and conditions of the nervous system, kidneys, and cardiovascular system in combination with the lack of major adverse effects of TRPC knockout or TRPC channel inhibition is driving the search of TRPC channel modulators as potential therapeutics. Here, we review the most promising small-molecule TRPC channel modulators, the understanding of their mode of action, and their potential in the study and treatment of cardiovascular and metabolic disease. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity

“…Transient receptor potential canonical (TRPC) proteins, regulating intracellular Ca 2+ , K + , and Na + , are involved in a variety of physiological and pathological processes in cardiovascular system (64). It has been reported that TRPC3 is a risk factor deteriorating the pathological cardiac remodeling (65,66).…”

BTDAzo: A Photoswitchable TRPC5 Channel Activator**

“…Following the proof-of-concept brain slice assay we have tested, we consider BTDAzo as a valuable tool to investigate the various roles of TRPC5 (and so distinguish them from the distinct roles of TRPC4) in brain function, including their potential in the study and treatment of metabolic disease. [12] We believe this is also the first report of azobenzothiadiazines as photoswitches for cell biology. It can give favourably complete bidirectional photoswitching with rapid response under biologically available wavelengths, and its easy synthesis and handling recommend it for use towards other photopharmaceuticals.…”

Nonselective TRPC channel inhibition and suppression of aminoglycoside-induced premature termination codon readthrough by the small molecule AC1903

“…To find out the possible contribution of genetic variants to this variation, we searched exome sequencing data in COSMIC ( https://cancer.sanger.ac.uk/cosmic ) and identified a hemizygous p.R175H missense mutation in TRPC5 in the TC-71 cell line not present in the DMS-114 cell line. This gene encodes the protein TRPC5, which forms homo- and heterotetrameric, nonselective cation channels permeable by Ca 2+ and Na + ( 31 , 32 , 33 , 34 , 35 , 36 , 37 ). Based on several pathogenicity prediction algorithms including SIFT ( 38 ) and PolyPhen-2 ( 39 ), this mutation is considered tolerable and benign.…”

“…High-quality chemical probes are powerful tools in target validation studies and can serve as useful starting points for drug development, especially when combined with genetic approaches. In our recent reviews, we highlighted the use of small-molecule modulators of TRPC1/4/5 channels to complement genetic approaches in dissecting the different roles of specific TRPC1/4/5 channels across species, tissues, and pathologies ( 36 , 37 ). However, even high-quality chemical probes are likely to have off-targets, and potency and selectivity of a chemical probe may be dependent on factors such as cellular context, mode of application, and treatment time.…”