Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition.
Tissue injury generates endogenous factors that heighten our sense of pain by increasing the response of sensory nerve endings to noxious stimuli. 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 neurons. 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-gamma 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.
Chuang
H H
HH
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143-0450, USA.
Prescott
E D
ED
Kong
H
H
Shields
S
S
Jordt
S E
SE
Basbaum
A I
AI
Chao
M V
MV
Julius
D
D
D000818:Animals; D001920:Bradykinin / Q000502:physiology*; D002460:Cell Line; D004594:Electrophysiology; D004789:Enzyme Activation; D005260:Female; D006358:Hot Temperature; D008297:Male; D051379:Mice; D020932:Nerve Growth Factor / Q000502:physiology*; D009619:Nociceptors / Q000378:metabolism; D009865:Oocytes / Q000502:physiology; D010146:Pain; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D020917:Receptor, trkA / Q000502:physiology; D011955:Receptors, Drug / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000502:physiology; D014982:Xenopus laevis
D019269:Phosphatidylinositol 4,5-Diphosphate; D011955:Receptors, Drug; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D011493:Protein Kinase C; D010738:Type C Phospholipases; D001920:Bradykinin