TRPA1 as a drug target—promise and challenges

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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.

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Structure of the TRPV1 ion channel determined by electron cryo-microscopy

Maofu Liao, Erhu Cao, David Julius … (2013)

Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to physical and chemical stimuli has been hampered by a lack of detailed structural information. Here, we exploit advances in electron cryo-microscopy to determine the structure of a mammalian TRP channel, TRPV1, at 3.4Å resolution, breaking the side-chain resolution barrier for membrane proteins without crystallization. Like voltage-gated channels, TRPV1 exhibits four-fold symmetry around a central ion pathway formed by transmembrane helices S5–S6 and the intervening pore loop, which is flanked by S1–S4 voltage sensor-like domains. TRPV1 has a wide extracellular ‘mouth’ with short selectivity filter. The conserved ‘TRP domain’ interacts with the S4–S5 linker, consistent with its contribution to allosteric modulation. Subunit organization is facilitated by interactions among cytoplasmic domains, including N-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.

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TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.

Diana Bautista, Sven-Eric Jordt, Tetsuro Nikai … (2006)

TRPA1 is an excitatory ion channel targeted by pungent irritants from mustard and garlic. TRPA1 has been proposed to function in diverse sensory processes, including thermal (cold) nociception, hearing, and inflammatory pain. Using TRPA1-deficient mice, we now show that this channel is the sole target through which mustard oil and garlic activate primary afferent nociceptors to produce inflammatory pain. TRPA1 is also targeted by environmental irritants, such as acrolein, that account for toxic and inflammatory actions of tear gas, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents. TRPA1-deficient mice display normal cold sensitivity and unimpaired auditory function, suggesting that this channel is not required for the initial detection of noxious cold or sound. However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity. Thus, TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain.

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Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin.

Michael Bandell, Gina M Story, Sun Wook Hwang … (2004)

Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temperature thresholds. The natural compounds capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, respectively. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. We show that, in addition to noxious cold, pungent natural compounds present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. We further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential molecular model for why noxious cold can paradoxically be perceived as burning pain.

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Author and article information

Contributors

Jun Chen: chenj144@gene.com

David H. Hackos: hackos.david@gene.com

Journal

Journal ID (nlm-ta): Naunyn Schmiedebergs Arch Pharmacol

Journal ID (iso-abbrev): Naunyn Schmiedebergs Arch. Pharmacol

Title: Naunyn-Schmiedeberg's Archives of Pharmacology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0028-1298

ISSN (Electronic): 1432-1912

Publication date (Electronic): 3 February 2015

Publication date PMC-release: 3 February 2015

Publication date (Print): 2015

Volume: 388

Issue: 4

Pages: 451-463

Affiliations

[ ]Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080 USA

[ ]Department of Neuroscience, Genentech, South San Francisco, CA 94080 USA

Article

Publisher ID: 1088

DOI: 10.1007/s00210-015-1088-3

PMC ID: 4359712

PubMed ID: 25640188

SO-VID: 27f00911-4ec0-4bed-8d76-1353bd57446c

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.