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Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation.
Br J Pharmacol. 2012 Jun; 166(4):1433-43.BJ

Abstract

BACKGROUND AND PURPOSE

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.

EXPERIMENTAL APPROACH

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.

KEY 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 AND IMPLICATIONS

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.

Authors+Show Affiliations

Korea University Graduate School of Medicine, Seoul, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22300296

Citation

Bang, S, et al. "Nociceptive and Pro-inflammatory Effects of Dimethylallyl Pyrophosphate Via TRPV4 Activation." British Journal of Pharmacology, vol. 166, no. 4, 2012, pp. 1433-43.
Bang S, Yoo S, Yang TJ, et al. Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation. Br J Pharmacol. 2012;166(4):1433-43.
Bang, S., Yoo, S., Yang, T. J., Cho, H., & Hwang, S. W. (2012). Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation. British Journal of Pharmacology, 166(4), 1433-43. https://doi.org/10.1111/j.1476-5381.2012.01884.x
Bang S, et al. Nociceptive and Pro-inflammatory Effects of Dimethylallyl Pyrophosphate Via TRPV4 Activation. Br J Pharmacol. 2012;166(4):1433-43. PubMed PMID: 22300296.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation. AU - Bang,S, AU - Yoo,S, AU - Yang,T J, AU - Cho,H, AU - Hwang,S W, PY - 2012/2/4/entrez PY - 2012/2/4/pubmed PY - 2012/10/10/medline SP - 1433 EP - 43 JF - British journal of pharmacology JO - Br J Pharmacol VL - 166 IS - 4 N2 - BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 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 AND IMPLICATIONS: 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/22300296/Nociceptive_and_pro_inflammatory_effects_of_dimethylallyl_pyrophosphate_via_TRPV4_activation_ L2 - https://doi.org/10.1111/j.1476-5381.2012.01884.x DB - PRIME DP - Unbound Medicine ER -