Proinflammatory Mediators Modulate the Heat-Activated Ion Channel TRPV1 via the Scaffolding Protein AKAP79/150

• Published in: Neuron (Cambridge, Mass.) Mass.), 2008-08, Vol.59 (3), p.450-461
• Main Authors: Zhang, Xuming, Li, Lin, McNaughton, Peter A.
• Format: Article
• Language: English
• Subjects: A Kinase Anchor Proteins - metabolism; Animals; Binding sites; Bradykinin - pharmacology; CELLBIO; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases - physiology; Dinoprostone - pharmacology; Dose-Response Relationship, Radiation; Electric Stimulation - methods; Experiments; Ganglia, Spinal - cytology; Heat; Hot Temperature; Humans; Kinases; Membrane Potentials - drug effects; Membrane Potentials - physiology; Membrane Potentials - radiation effects; Models, Biological; MOLIMMUNO; MOLNEURO; Mutation - physiology; Neurons; Neurons, Afferent - drug effects; Neurons, Afferent - metabolism; Patch-Clamp Techniques; Peptides; Phosphorylation; Protein Binding - drug effects; Protein Kinase C - physiology; Proteins; Rats; RNA, Small Interfering - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; Temperature; Transfection; TRPV Cation Channels - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2008.05.015

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.