TRPV1 is a novel target for omega-3 polyunsaturated fatty acids.
Omega-3 (n-3) fatty acids are essential for proper neuronal function, and they possess prominent analgesic properties, yet their underlying signalling mechanisms are unclear. Here we show that n-3 fatty acids interact directly with TRPV1, an ion channel expressed in nociceptive neurones and brain. These fatty acids activate TRPV1 in a phosphorylation-dependent manner, enhance responses to extracellular protons, and displace binding of the ultrapotent TRPV1 ligand [3H]resiniferatoxin. In contrast to their agonistic properties, n-3 fatty acids competitively inhibit the responses of vanilloid agonists. These actions occur in mammalian cells in the physiological concentration range of 1-10 mum. Significantly, docosahexaenoic acid exhibits the greatest efficacy as an agonist, whereas eicosapentaenoic acid and linolenic acid are markedly more effective inhibitors. Similarly, eicosapentaenoic acid but not docosahexaenoic acid profoundly reduces capsaicin-evoked pain-related behaviour in mice. These effects are independent of alterations in membrane elasticity because the micelle-forming detergent Triton X-100 only minimally affects TRPV1 properties. Thus, n-3 fatty acids differentially regulate TRPV1 and this form of signalling may contribute to their biological effects. Further, these results suggest that dietary supplementation with selective n-3 fatty acids would be most beneficial for the treatment of pain.
Matta
José A
JA
Department of Pharmacology, Georgetown University, Washington, DC 20007, USA.
Miyares
Rosa L
RL
Ahern
Gerard P
GP
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D043371:Fatty Acids, Omega-6 / Q000494:pharmacology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019787:Linoleic Acid / Q000494:pharmacology; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D050916:TRPV Cation Channels / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis
D004224:Diterpenes; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D018075:RNA, Complementary; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D019787:Linoleic Acid; C024353:resiniferatoxin; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium