Editors' ChoiceNeurobiology

PIP2 Controls Pain

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Science's STKE  26 Jun 2001:
Vol. 2001, Issue 88, pp. tw3
DOI: 10.1126/stke.2001.88.tw3

The vanilloid receptor (VR1) is involved in pain perception caused by heat and various chemicals, such as capsaicin. Various factors produced during inflammatory responses, including extracellular protons, growth factors, and neurotransmitters, make sensory neurons more sensitive to noxious stimuli. Mice in which the VR1 gene is disrupted do not become sensitized to pain in response to the neurotransmitter bradykinin (BK) or nerve growth factor (NGF), two agents known to decrease the threshold of sensory neurons, which activate receptors coupled to phospholipase C (PLC). The mechanism underlying this lack of hypersensitivity was investigated by using transfected cells or microinjected oocytes. Application of BK or NGF increased VR1 channel activity in response to low pH, heat, and capsaicin. The effect of NGF was dependent on coexpression of the TrkA receptor for NGF competent to activate PLC, because mutant forms of the TrkA receptor that could not activate PLC did not enhance VR1 channel activity. Application of recombinant PLC to excised patches of VR1-expressing cells mimicked the effects of NGF or BK. Using an antibody against phosphatidylinositol-4,5-bisphosphate (PIP2), which sequesters PIP2 and mimics the effect of activation of PLC, Chuang et al. show that decreased levels of PIP2 lead to VR1 activation and sensitization of VR1-mediated responses to heat, low pH, and capsaicin. Thus, through alteration of the lipid environment surrounding VR1, diverse extracellular factors can regulate nociception.

H.-h. Chuang, E. D. Prescott, H. Kong, S. Shields, S.-E. Jordt, A. I. Basbaum, M. C. Chao, D. Julius, Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957-962 (2001). [Online Journal]

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