Journal club 2012-10-26

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TRPV1 is a novel target for omega-3 polyunsaturated fatty acids

tjp0578-0397

Jose ́ A. Matta, Rosa L. Miyares and Gerard P. Ahern

From the Department of Pharmacology, Georgetown University, Washington, DC 20007, USA

Omega-3 (n-3) fatty acids are essential for proper neuronal function, and they possess prominent analgesic properties, yet their underlying signalling mechanisms are unclear. Here we show that n-3 fatty acids interact directly with TRPV1, an ion channel expressed in nociceptive neurones and brain. These fatty acids activate TRPV1 in a phosphorylation-dependent manner, enhance responses to extracellular protons, and displace binding of the ultrapotent TRPV1 ligand [3 H]resiniferatoxin. In contrast to their agonistic properties, n-3 fatty acids competitively inhibit the responses of vanilloid agonists. These actions occur in mammalian cells in the physiological concentration range of 1–10 μM. Significantly, docosahexaenoic acid exhibits the greatest efficacy as an agonist, whereas eicosapentaenoic acid and linolenic acid are markedly more effective inhibitors. Similarly, eicosapentaenoic acid but not docosahexaenoic acid profoundly reduces capsaicin-evoked pain-related behaviour in mice. These effects are independent of alterations in membrane elasticity because the micelle-forming detergent Triton X-100 only minimally affects TRPV1 properties. Thus, n-3 fatty acids differentially regulate TRPV1 and this form of signalling may contribute to their biological effects. Further, these results suggest that dietary supplementation with selective n-3 fatty acids would be most beneficial for the treatment of pain.

(Resubmitted 28 September 2006; accepted 8 October 2006; first published online 12 October 2006)
Corresponding author G. P. Ahern: Department of Pharmacology, Georgetown University, MedDent SW401, 3900 Reservoir Rd, Washington, DC 20007, USA. Email: gpa3@georgetown.edu

 

Journal club 2012-09-27

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pone.0038439

TRPA1 Is a Polyunsaturated Fatty Acid Sensor in Mammals

Arianne L. Motter, Gerard P. Ahern*
Department of Pharmacology and Physiology, Georgetown University, Washington, District of Columbia, United States of America

Abstract

Fatty acids can act as important signaling molecules regulating diverse physiological processes. Our understanding, however, of fatty acid signaling mechanisms and receptor targets remains incomplete. Here we show that Transient Receptor Potential Ankyrin 1 (TRPA1), a cation channel expressed in sensory neurons and gut tissues, functions as a sensor of polyunsaturated fatty acids (PUFAs) in vitro and in vivo. PUFAs, containing at least 18 carbon atoms and three unsaturated bonds, activate TRPA1 to excite primary sensory neurons and enteroendocrine cells. Moreover, behavioral aversion to PUFAs is absent in TRPA1-null mice. Further, sustained or repeated agonism with PUFAs leads to TRPA1 desensitization. PUFAs activate TRPA1 non-covalently and independently of known ligand binding domains located in the N-terminus and 5th transmembrane region. PUFA sensitivity is restricted to mammalian (rodent and human) TRPA1 channels, as the drosophila and zebrafish TRPA1 orthologs do not respond to DHA. We propose that PUFA-sensing by mammalian TRPA1 may regulate pain and gastrointestinal functions.

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Citation: Motter AL, Ahern GP (2012) TRPA1 Is a Polyunsaturated Fatty Acid Sensor in Mammals. PLoS ONE 7(6): e38439. doi:10.1371/journal.pone.0038439

Editor: Stuart E. Dryer, University of Houston, United States of America

Received November 3, 2011; Accepted May 7, 2012; Published June 19, 2012

Copyright: ß 2012 Motter, Ahern. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by grants from National Institute of Neurological Disorders and Stroke and the American Recovery and Reinvestment Act 2009. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.
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