Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation.
OBJECTIVE
Sensory neuronal and epidermal transient receptor potential ion channels (TRPs) serve an important role as pain sensor molecules. While many natural and synthetic ligands for sensory TRPs have been identified, little is known about the endogenous activator for TRPV4. Recently, we reported that endogenous metabolites produced by the mevalonate pathway regulate the activities of sensory neuronal TRPs. Here, we show that dimethylallyl pyrophosphate (DMAPP), a substance produced by the same pathway is an activator of TRPV4.


METHODS
We examined the effects of DMAPP on sensory TRPs using Ca²⁺ imaging and whole-cell electrophysiology experiments with a heterologous expression system (HEK293T cells transfected with individual TRP channels), cultured sensory neurons and keratinocytes. We then evaluated nociceptive behavioural and inflammatory changes upon DMAPP administration in mice in vivo.


RESULTS
In the HEK cell heterologous expression system, cultured sensory neurons and keratinocytes, µM concentrations of DMAPP activated TRPV4. Agonistic and antagonistic potencies of DMAPP for other sensory TRP channels were examined and activation of TRPV3 by camphor was found to be inhibited by DMAPP. In vivo assays, intraplantar injection of DMAPP acutely elicited nociceptive flinches that were prevented by pretreatment with TRPV4 blockers, indicating that DMAPP is a novel pain-producing molecule through TRPV4 activation. Further, DMAPP induced acute inflammation and noxious mechanical hypersensitivities in a TRPV4-dependent manner.


CONCLUSIONS
Overall, we found a novel sensory TRP acting metabolite and suggest that its use may help to elucidate the physiological role of TRPV4 in nociception and associated inflammation.
Korea University Graduate School of Medicine, Seoul, Korea.
S
S
Bang
S
S
Yoo
T J
TJ
Yang
H
H
Cho
S W
SW
Hwang
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D045782:Hemiterpenes / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009443:Neuritis / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D059226:Nociceptive Pain / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D020033:Protein Isoforms / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D045782:Hemiterpenes; D008024:Ligands; D009419:Nerve Tissue Proteins; D009943:Organophosphorus Compounds; D020033:Protein Isoforms; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels; C486576:Trpv4 protein, mouse; C043060:3,3-dimethylallyl pyrophosphate