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Acid potentiation of the capsaicin receptor determined by a key extracellular site

  1. David Julius‡
  1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-0450

  1. Communicated by Lily Y. Jan, University of California, San Francisco, CA (received for review February 7, 2000)

Abstract

The capsaicin (vanilloid) receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. The response of VR1 to capsaicin or noxious heat is dynamically potentiated by extracellular protons within a pH range encountered during tissue acidosis, such as that associated with arthritis, infarction, tumor growth, and other forms of injury. A molecular determinant for this important physiological activity was localized to an extracellular Glu residue (E600) in the region linking the fifth transmembrane domain with the putative pore-forming region of the channel. We suggest that this residue serves as a key regulatory site of the receptor by setting sensitivity to other noxious stimuli in response to changes in extracellular proton concentration. We also demonstrate that protons, vanilloids, and heat promote channel opening through distinct pathways, because mutations at a second site (E648) selectively abrogate proton-evoked channel activation without diminishing responses to other noxious stimuli. Our findings provide molecular evidence for stimulus-specific steps in VR1 activation and offer strategies for the development of novel analgesic agents.

Footnotes

    • ↵* These authors contributed equally to this work.

    • ↵† Present address: Department of Molecular Neurobiology, Institute of Basic Medical Sciences, University of Tsukuba, Tennoudai 1–1-1, Tsukuba, Iabaraki 305-8575, Japan.

    • ↵‡ To whom reprint requests should be addressed. E-mail: julius{at}socrates.ucsf.edu.

    • Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.100129497.

    • Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.100129497

  • Abbreviation

    VR1,
    capsaicin (vanilloid) receptor
    • Received February 7, 2000.
    • Accepted March 23, 2000.

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