Transient receptor potential (TRP) channels: a clinical perspective

Abstract

Transient receptor potential (TRP) channels are important mediators of sensory signals with marked effects on cellular functions and signalling pathways. Indeed, mutations in genes encoding TRP channels are the cause of several inherited diseases in humans (the so-called 'TRP channelopathies') that affect the cardiovascular, renal, skeletal and nervous systems. TRP channels are also promising targets for drug discovery. The initial focus of research was on TRP channels that are expressed on nociceptive neurons. Indeed, a number of potent, small-molecule TRPV1, TRPV3 and TRPA1 antagonists have already entered clinical trials as novel analgesic agents. There has been a recent upsurge in the amount of work that expands TRP channel drug discovery efforts into new disease areas such as asthma, cancer, anxiety, cardiac hypertrophy, as well as obesity and metabolic disorders. A better understanding of TRP channel functions in health and disease should lead to the discovery of first-in-class drugs for these intractable diseases. With this review, we hope to capture the current state of this rapidly expanding and changing field.

Keywords: TRP channels; TRPA1; TRPCs; TRPM8; TRPV1; TRPV3; TRPV4; bladder disorders; cancer; pain; respiratory disorders.

Figure 1

Simplified topographical structure of TRP channels (A). Please note the similarities and differences between TRP channel subfamilies (B). Reprinted, with permission, from Nilius and Owsianik (2011).

Figure 2

Schematic illustration of the tissue-distribution of TRP channels and their putative roles in the pathogenesis of human disease.

Figure 3

Selected TRPV1 agonists: capsaicin (the pungent ingredient in hot chili peppers), resiniferatoxin (isolated from the cactus-like perennial E. resinifera), and the endocannabinoids anandamide and palmitoylethanolamide.

Figure 4

Small molecule TRPV1 antagonists: selected structures.

Figure 5

Representative examples of TRPV4 agonists (GSK1016790A), TRPV4 antagonists (HC-067047), TRPV3 agonists (2-ABT), and TRPC3 inhibitors (Pyr3).

Figure 6

Selected plant cannabinoids that target TRP channels: cannabichromene (TRPA1 agonist) and cannabidiol (TRPM8 antagonist).