NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels.
Nociceptors, or pain-sensitive receptors, are unique among sensory receptors in that their sensitivity is increased by noxious stimulation. This process, called sensitization or hyperalgesia, is mediated by a variety of proinflammatory factors, including bradykinin, ATP and NGF, which cause sensitization to noxious heat stimuli by enhancing the membrane current carried by the heat- and capsaicin-gated ion channel, TRPV1. Several different mechanisms for sensitization of TRPV1 have been proposed. Here we show that NGF, acting on the TrkA receptor, activates a signalling pathway in which PI3 kinase plays a crucial early role, with Src kinase as the downstream element which binds to and phosphorylates TRPV1. Phosphorylation of TRPV1 at a single tyrosine residue, Y200, followed by insertion of TRPV1 channels into the surface membrane, explains most of the rapid sensitizing actions of NGF.
Zhang
Xuming
X
Department of Pharmacology, University of Cambridge, Cambridge, UK.
Huang
Jiehong
J
McNaughton
Peter A
PA
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004594:Electrophysiology; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007473:Ion Channels; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D020932:Nerve Growth Factor / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D020917:Receptor, trkA / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D012964:Sodium / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D014638:Vanadates / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
D018076:DNA, Complementary; D007473:Ion Channels; D011993:Recombinant Fusion Proteins; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; C076715:pervanadate; D014638:Vanadates; D014443:Tyrosine; D004247:DNA; D020932:Nerve Growth Factor; D012964:Sodium; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; D020917:Receptor, trkA; D019061:src-Family Kinases; D002211:Capsaicin; D002118:Calcium