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The tyrosine kinase inhibitor bafetinib inhibits PAR2-induced activation of TRPV4 channels in vitro and pain in vivo.
Br J Pharmacol. 2014 Aug; 171(16):3881-94.BJ

Abstract

BACKGROUND AND PURPOSE

Protease-activated receptor 2 (PAR2) is expressed on nociceptive neurons, and can sensitize transient receptor potential (TRP) ion channels to amplify neurogenic inflammation and pain. The mechanisms by which this occurs are not fully understood. PAR2 causes receptor-operated activation of TRPV4 channels and TRPV4 null mice have attenuated PAR2-stimulated neurogenic inflammation and mechanical hyperalgesia. Here we investigate the intracellular signalling mechanisms underlying PAR2-induced TRPV4 channel activation and pain.

EXPERIMENTAL APPROACH

Responses of non-transfected and TRPV4-transfected HEK293 cells to agonists of PAR2 (trypsin and SLIGRL) and TRPV4 channels (GSK1016790A) were determined using calcium imaging. Inhibitors of TRPV4 channels (HC067047), sarcoendoplasmic reticulum calcium transport ATPase (thapsigargin), Gαq (UBO-QIC), tyrosine kinases (bafetinib and dasatinib) or PI3 kinases (wortmannin and LY294002) were used to investigate signalling mechanisms. In vivo effects of tyrosine kinase inhibitors on PAR2 -induced mechanical hyperalgesia were assessed in mice.

KEY RESULTS

In non-transfected HEK293 cells, PAR2 activation transiently increased intracellular calcium ([Ca(2+) ]i). Functional expression of TRPV4 channels caused a sustained increase of [Ca(2+) ]i , inhibited by HC067047, bafetinib and wortmannin; but not by thapsigargin, UBO-QIC, dasatinib or LY294002. Bafetinib but not dasatinib inhibited PAR2-induced mechanical hyperalgesia in vivo.

CONCLUSIONS AND IMPLICATIONS

This study supports a role for tyrosine kinases in PAR2-mediated receptor-operated gating of TRPV4 channels, independent of Gαq stimulation. The ability of a tyrosine kinase inhibitor to diminish PAR2-induced activation of TRPV4 channels and consequent mechanical hyperalgesia identifies bafetinib (which is in development in oncology) as a potential novel analgesic therapy.

Authors+Show Affiliations

School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.No affiliation info availableNo affiliation info availableNo 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

24779362

Citation

Grace, M S., et al. "The Tyrosine Kinase Inhibitor Bafetinib Inhibits PAR2-induced Activation of TRPV4 Channels in Vitro and Pain in Vivo." British Journal of Pharmacology, vol. 171, no. 16, 2014, pp. 3881-94.
Grace MS, Lieu T, Darby B, et al. The tyrosine kinase inhibitor bafetinib inhibits PAR2-induced activation of TRPV4 channels in vitro and pain in vivo. Br J Pharmacol. 2014;171(16):3881-94.
Grace, M. S., Lieu, T., Darby, B., Abogadie, F. C., Veldhuis, N., Bunnett, N. W., & McIntyre, P. (2014). The tyrosine kinase inhibitor bafetinib inhibits PAR2-induced activation of TRPV4 channels in vitro and pain in vivo. British Journal of Pharmacology, 171(16), 3881-94. https://doi.org/10.1111/bph.12750
Grace MS, et al. The Tyrosine Kinase Inhibitor Bafetinib Inhibits PAR2-induced Activation of TRPV4 Channels in Vitro and Pain in Vivo. Br J Pharmacol. 2014;171(16):3881-94. PubMed PMID: 24779362.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The tyrosine kinase inhibitor bafetinib inhibits PAR2-induced activation of TRPV4 channels in vitro and pain in vivo. AU - Grace,M S, AU - Lieu,T, AU - Darby,B, AU - Abogadie,F C, AU - Veldhuis,N, AU - Bunnett,N W, AU - McIntyre,P, PY - 2014/02/27/received PY - 2014/04/02/revised PY - 2014/04/17/accepted PY - 2014/5/1/entrez PY - 2014/5/2/pubmed PY - 2015/4/10/medline SP - 3881 EP - 94 JF - British journal of pharmacology JO - Br J Pharmacol VL - 171 IS - 16 N2 - BACKGROUND AND PURPOSE: Protease-activated receptor 2 (PAR2) is expressed on nociceptive neurons, and can sensitize transient receptor potential (TRP) ion channels to amplify neurogenic inflammation and pain. The mechanisms by which this occurs are not fully understood. PAR2 causes receptor-operated activation of TRPV4 channels and TRPV4 null mice have attenuated PAR2-stimulated neurogenic inflammation and mechanical hyperalgesia. Here we investigate the intracellular signalling mechanisms underlying PAR2-induced TRPV4 channel activation and pain. EXPERIMENTAL APPROACH: Responses of non-transfected and TRPV4-transfected HEK293 cells to agonists of PAR2 (trypsin and SLIGRL) and TRPV4 channels (GSK1016790A) were determined using calcium imaging. Inhibitors of TRPV4 channels (HC067047), sarcoendoplasmic reticulum calcium transport ATPase (thapsigargin), Gαq (UBO-QIC), tyrosine kinases (bafetinib and dasatinib) or PI3 kinases (wortmannin and LY294002) were used to investigate signalling mechanisms. In vivo effects of tyrosine kinase inhibitors on PAR2 -induced mechanical hyperalgesia were assessed in mice. KEY RESULTS: In non-transfected HEK293 cells, PAR2 activation transiently increased intracellular calcium ([Ca(2+) ]i). Functional expression of TRPV4 channels caused a sustained increase of [Ca(2+) ]i , inhibited by HC067047, bafetinib and wortmannin; but not by thapsigargin, UBO-QIC, dasatinib or LY294002. Bafetinib but not dasatinib inhibited PAR2-induced mechanical hyperalgesia in vivo. CONCLUSIONS AND IMPLICATIONS: This study supports a role for tyrosine kinases in PAR2-mediated receptor-operated gating of TRPV4 channels, independent of Gαq stimulation. The ability of a tyrosine kinase inhibitor to diminish PAR2-induced activation of TRPV4 channels and consequent mechanical hyperalgesia identifies bafetinib (which is in development in oncology) as a potential novel analgesic therapy. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/24779362/The_tyrosine_kinase_inhibitor_bafetinib_inhibits_PAR2_induced_activation_of_TRPV4_channels_in_vitro_and_pain_in_vivo_ L2 - https://doi.org/10.1111/bph.12750 DB - PRIME DP - Unbound Medicine ER -