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Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition

Author

Listed:
  • Huai-hu Chuang

    (University of California)

  • Elizabeth D. Prescott

    (University of California)

  • Haeyoung Kong

    (Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

  • Shannon Shields

    (University of California)

  • Sven-Eric Jordt

    (University of California)

  • Allan I. Basbaum

    (University of California)

  • Moses V. Chao

    (Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

  • David Julius

    (University of California)

Abstract

Tissue injury generates endogenous factors that heighten our sense of pain by increasing the response of sensory nerve endings to noxious stimuli1,2. Bradykinin and nerve growth factor (NGF) are two such pro-algesic agents that activate G-protein-coupled (BK2) and tyrosine kinase (TrkA) receptors, respectively, to stimulate phospholipase C (PLC) signalling pathways in primary afferent neurons3,4. How these actions produce sensitization to physical or chemical stimuli has not been elucidated at the molecular level. Here, we show that bradykinin- or NGF-mediated potentiation of thermal sensitivity in vivo requires expression of VR1, a heat-activated ion channel on sensory neurons. Diminution of plasma membrane phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) levels through antibody sequestration or PLC-mediated hydrolysis mimics the potentiating effects of bradykinin or NGF at the cellular level. Moreover, recruitment of PLC-γ to TrkA is essential for NGF-mediated potentiation of channel activity, and biochemical studies suggest that VR1 associates with this complex. These studies delineate a biochemical mechanism through which bradykinin and NGF produce hypersensitivity and might explain how the activation of PLC signalling systems regulates other members of the TRP channel family.

Suggested Citation

  • Huai-hu Chuang & Elizabeth D. Prescott & Haeyoung Kong & Shannon Shields & Sven-Eric Jordt & Allan I. Basbaum & Moses V. Chao & David Julius, 2001. "Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition," Nature, Nature, vol. 411(6840), pages 957-962, June.
    • Handle: RePEc:nat:nature:v:411:y:2001:i:6840:d:10.1038_35082088
    DOI: 10.1038/35082088
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