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Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site

Nature Chemical Biology volume 8, pages 78–85 (2012)Cite this article

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A Corrigendum to this article was published on 18 July 2012

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Abstract

Since 1992, there has been growing evidence that the bioactive phospholipid lysophosphatidic acid (LPA), whose amounts are increased upon tissue injury, activates primary nociceptors resulting in neuropathic pain. The TRPV1 ion channel is expressed in primary afferent nociceptors and is activated by physical and chemical stimuli. Here we show that in control mice LPA produces acute pain-like behaviors, which are substantially reduced in Trpv1-null animals. Our data also demonstrate that LPA activates TRPV1 through a unique mechanism that is independent of G protein–coupled receptors, contrary to what has been widely shown for other ion channels, by directly interacting with the C terminus of the channel. We conclude that TRPV1 is a direct molecular target of the pain-producing molecule LPA and that this constitutes, to our knowledge, the first example of LPA binding directly to an ion channel to acutely regulate its function.

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Figure 1: TRPV1 responds to LPA.
Figure 2: Heterologously expressed TRPV1 channels respond to LPA.
Figure 3: An antagonist of LPA receptors with a similar structure to LPA activates TRPV1.
Figure 4: Interaction site for LPA in the C terminus of TRPV1.

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Change history

  • 15 June 2012

    In the version of this article initially published, the amount of LPA used in behavioral assays was incorrectly stated in the Methods section as 3 μg when it should have read 4.1 μg. Also, the details of preparation of LPA stock solutions were incomplete in the Methods section. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank D. Julius at University of California, San Francisco for providing the TRPV1 and TRPV2 cDNA, A. Patapoutian at the Scripps Research Institute for the TRPA1 cDNA, A. Toker at Harvard Medical School for PKCɛ dominant-negative and wild-type plasmids, J.A. García-Sáinz for his kind gift of BIM I and M. Calcagno for helpful discussion. We also thank L. Ongay, A. Escalante and F. Pérez at Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM) for expert technical support and F. Sierra for expert help with DRG neuron culture. We are grateful to C.C. Durán and V.G. Soto for very valuable help with paw-withdrawal experiments. This work was supported by Dirección General de Asuntos del Personal Académico–Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (DGAPA-PAPIIT) grant IN209209 and Instituto de Ciencia y Tecnología del Distrito Federal (ICYT-DF) grant PIFUTP09-262 to L.D.I., PAPIIT grants IN216009 and CONACyT 53777 to D.E.-A., and PAPIIT grants IN294111-3 and CONACyT CB-129474 and a grant from Fundación Miguel Alemán to T.R. This study was performed in partial fulfillment of the requirements for A.N.-P.'s doctoral degree in biomedical sciences at the UNAM.

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Authors and Affiliations

  1. Departamento de Neurodesarrollo y Fisiología, División Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Distrito Federal, México

    Andrés Nieto-Posadas, Giovanni Picazo-Juárez, Itzel Llorente, Sara Morales-Lázaro, Diana Escalante-Alcalde & Tamara Rosenbaum

  2. Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Distrito Federal, México

    Andrés Jara-Oseguera & León D Islas

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  1. Andrés Nieto-Posadas
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Contributions

A.N.-P., G.P.-J. and A.J.-O. performed electrophysiological experiments. I.L. carried out all site-directed mutagenesis. S.M.-L. performed all animal matings, genotyping and biochemical assays. D.E.-A., L.D.I. and T.R. jointly conceived the study, performed recordings and analysis, and wrote the paper.

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Correspondence to Diana Escalante-Alcalde, León D Islas or Tamara Rosenbaum.

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Nieto-Posadas, A., Picazo-Juárez, G., Llorente, I. et al. Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site. Nat Chem Biol 8, 78–85 (2012). https://doi.org/10.1038/nchembio.712

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