Canonical transient receptor potential channels and their modulators: biology, pharmacology and therapeutic potentials

Abstract

Canonical transient receptor potential channels (TRPCs) are nonselective, high calcium permeability cationic channels. The TRPCs family includes TRPC1, TRPC2, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7. These channels are widely expressed in the cardiovascular and nervous systems and exist in many other human tissues and cell types, playing several crucial roles in the human physiological and pathological processes. Hence, the emergence of TRPCs modulators can help investigate these channels’ applications in health and disease. It is worth noting that the TRPCs subfamilies have structural and functional similarities, which presents a significant difficulty in screening and discovering of TRPCs modulators. In the past few years, only a limited number of selective modulators of TRPCs were detected; thus, additional research on more potent and more selective TRPCs modulators is needed. The present review focuses on the striking desired therapeutic effects of TRPCs modulators, which provides intel on the structural modification of TRPCs modulators and further pharmacological research. Importantly, TRPCs modulators can significantly facilitate future studies of TRPCs and TRPCs related diseases.

Interactions between the Polysialylated Neural Cell Adhesion Molecule and the Transient Receptor Potential Canonical Channels 1, 4, and 5 Induce Entry of Ca2+ into Neurons

“…Since Pico145, but not HC-070, inhibits the NCAM antibody-triggered Ca 2+ entry into neurons, the question arises as to the mechanisms of this difference. Although Pico145 and HC-070 are both xanthine derivatives and inhibit TRPC1, −4, and −5 channels with similar high potency [ 61 , 62 , 63 ], Pico145 and HC-070 bind to different sites on TRPC1, −4, and −5: Pico145 binds to lipid-binding sites thereby displacing phospholipids [ 64 ] that interact with the pore-forming helices of these TRPCs, while HC-070 binds to sites between adjacent TRPC molecules thereby replacing the glycerol group of DAG [ 65 ]. Thus, it is tempting to speculate that the phospholipids that are replaced by Pico145 are required for the binding of PSA to the ICD of TRPC1, −4, and −5 and, thus for the NCAM-induced opening of TRPCs, while the glycerol group of DAG that is replaced by HC-070 is not required for the binding of PSA to the ICD of these TRPCs and for the opening of these TRPCs.…”

TRPC3 Regulates Islet Beta‐Cell Insulin Secretion

“…The transient receptor potential canonical 3 (TRPC3) channels are non‐selective cation channels that belong to the canonical subfamily. [ 7 ] TRPC3 channels participate in physiological functions [ 11 ] and are also involved in a variety of diseases. [ 12–14 ] TRPC3 channels have proven function in the pancreas but only in the exocrine acini.…”

Identification of molecular subtypes and prognostic signatures based on transient receptor potential channel-related genes to predict the prognostic risk of hepatocellular carcinoma: A review

“…[14] The mammalian TRP superfamily consists of 28 nonselective cation-permeable channels that can be divided into 6 subfamilies based on sequence homology. [15] In cancer, mutations in TRP channel-encoding genes generate TRP channels with abnormal functions that interfere with normal intracellular Ca 2+ distribution patterns, resulting in the dysregulation Key Points 1. Two molecular subtypes of hepatocellular carcinoma were identified based on 16 transient receptor potential channel-related genes.…”

“…[14] The mammalian TRP superfamily consists of 28 nonselective cation-permeable channels that can be divided into 6 subfamilies based on sequence homology. [15] In cancer, mutations in TRP channel-encoding genes generate TRP channels with abnormal functions that interfere with normal intracellular Ca 2+ distribution patterns, resulting in the dysregulation of downstream effectors and enhanced cancer-specific pathological features. [16] For example, the expression of TRPV2 has been implicated in the drug-induced cytotoxicity and stemness of HCC.…”