Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150

TY - JOUR

T1 - Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150

AU - Zhang, Xuming

AU - Li, Lin

AU - McNaughton, Peter A.

PY - 2008/8/14

Y1 - 2008/8/14

N2 - The ability of vertebrates to detect and avoid damaging extremes of temperature depends on activation of ion channels belonging to the thermo-TRIP 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.

AB - The ability of vertebrates to detect and avoid damaging extremes of temperature depends on activation of ion channels belonging to the thermo-TRIP 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.

KW - CAPSAICIN RECEPTOR VR1

KW - ROOT GANGLION NEURONS

KW - VANILLOID RECEPTOR-1

KW - KINASE-II

KW - DIRECT PHOSPHORYLATION

KW - THERMAL HYPERALGESIA

KW - NOCICEPTIVE NEURONS

KW - EVOKED ACTIVATION

KW - SENSORY NEURONS

KW - DESENSITIZATION

U2 - 10.1016/j.neuron.2008.05.015

DO - 10.1016/j.neuron.2008.05.015

M3 - Article

SN - 0896-6273

VL - 59

SP - 450

EP - 461

JO - Neuron

JF - Neuron

IS - 3

ER -