Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150.
The ability of vertebrates to detect and avoid damaging extremes of temperature depends on activation of ion channels belonging to the thermo-TRP family. Injury or inflammation causes the release of inflammatory mediators which lower the threshold for detection of painful levels of heat, a process known as heat hyperalgesia. These inflammatory mediators act by at least three distinct intracellular signaling pathways. Here, we show that modulation of the sensitivity of the heat-activated ion channel TRPV1 by the protein kinases PKA and PKC and by the phosphatase calcineurin depends on the formation of a signaling complex between these enzymes, the scaffolding protein AKAP79/150 and TRPV1. We identify a critical region in the TRPV1 C-terminal which mediates binding of AKAP79/150. If binding is prevented, then sensitization by both bradykinin and PGE(2) is abrogated. AKAP79/150 is therefore a final common element in heat hyperalgesia, on which the effects of multiple proinflammatory mediators converge.
Zhang
Xuming
X
Department of Pharmacology, University of Cambridge, Cambridge CB21PD, UK.
Li
Lin
L
McNaughton
Peter A
PA
D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D015232:Dinoprostone / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology; D006358:Hot Temperature; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050916:TRPV Cation Channels / Q000378:metabolism*; D014162:Transfection
D054758:A Kinase Anchor Proteins; C415703:Akap5 protein, rat; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D015232:Dinoprostone; D001920:Bradykinin