TRPA1 as a drug target--promise and challenges

Abstract

The transient receptor potential ankyrin 1 (TRPA1) channel is a nonselective cation channel belonging to the superfamily of transient receptor potential (TRP) channels. It is predominantly expressed in sensory neurons and serves as an irritant sensor for a plethora of electrophilic compounds. Recent studies suggest that TRPA1 is involved in pain, itch, and respiratory diseases, and TRPA1 antagonists have been actively pursued as therapeutic agents. Here, we review the recent progress, unsettled issues, and challenges in TRPA1 research and drug discovery.

Fig. 1

Structure of the TRPA1 channel. The TRPA1 channel shares the overall architecture of voltage-gated ion channels. It is a homotetramer with each subunit containing six transmembrane helices and intracellular N- and C-termini (as shown). The transmembrane helices are labeled S1–S6 with S1–S4 representing the ancestral voltage-sensing domain (VSD) and S5–S6 forming the central pore and selectivity filter. The reactive lysine and cysteine residues are shown within the N-terminal domain, along with the N-terminal ankyrin repeats. Please note N855S, the residue mutated in familial episodic pain syndrome (FEPS), is shown on the intracellular end of S4 based on recent electron cryo-microscopy structure of TRPV1 (Liao et al. 2013) and comparison between TRPA1 and TRPV1 hydropathy plots, and the putative Ca⁺⁺ binding region is shown within the C-terminus

Fig. 2

Modulation of TRPA1. TRPA1 is modulated by in multiple ways and represents an integrator of nociceptive signals. Agonists bind to the channel (most but not all within the N-terminal domain) and result in direct activation. PIP₂ functions as an endogenous inhibitor which is removed by GPCR-dependent activation of PLC. PLC also liberates IP₃, resulting in release of Ca⁺⁺ from intracellular stores. Ca⁺⁺, either from stores or from influx through other channels such as TRPV1, positively modulates TRPA1 via an intracellular binding site which has not been fully elucidated. Cold and mechanical forces can also activate TRPA1 via mechanisms that are not well understood

Fig. 3

Examples of TRPA1 antagonists. HC-030031, AP18, and A-967079 are currently the most commonly used TRPA1 tool antagonists for studying TRPA1 biology in vivo and in vitro. A newer generation of TRPA1 antagonists (lower row) have recently been developed that offer better potency on the rodent TRPA1 channels as well as significantly improved PK properties compared to earlier generation compounds