Cathepsin S Causes Inflammatory Pain via Biased Agonism of PAR2 and TRPV4

Zhao, Peishen; Lieu, Tina Marie; Barlow, Νicholas; Metcalf, Matthew; Veldhuis, Nicholas A.; Jensen, Dane D.; Kočan, Martina; Sostegni, Silvia; Haerteis, Silke; Baraznenok, Vera; Henderson, Ian; Lindström, Erik; Guerrero-Alba, Raquel; Valdez-Moráles, Eduardo E.; Liedtke, Wolfgang; McIntyre, Peter; Vanner, Stephen; Korbmacher, Christoph; Bunnett, Nigel W.

doi:10.1074/jbc.m114.599712

Cited by 153 publications

(117 citation statements)

References 66 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…Other proteases, including cathepsin S and elastase, are biased agonists that cleave PAR 2 at distinct sites to induce coupling to G␣ s but not G␣ q or ␤-arrestins (23)(24)(25). Cathepsin S-and elastase-activated PAR 2 cannot be reactivated by proteolysis, but the cleaved receptors remain at the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…Perforated patch clamp recording were made from small diameter neurons (Ͻ30 picofarad capacitance). Changes in excitability were quantified by measuring rheobase and number of action potential discharges at twice rheobase, as described (23). Cells were incubated for 10 min with trypsin (50 nM) or vehicle (control) and were then transferred to F-12 medium.…”

Section: Methodsmentioning

confidence: 99%

“…Patch Clamp Studies of Nociceptors-Dorsal root ganglia (T9 -T13) from C57BL/6 mice were dispersed and cultured overnight as described (23). Perforated patch clamp recording were made from small diameter neurons (Ͻ30 picofarad capacitance).…”

Section: Methodsmentioning

confidence: 99%

“…PAR 2 activates PKD in nociceptors (27) but with unknown functional relevance. Because PAR 2 -activating proteases induce hyperexcitability of nociceptors (23,24), we investigated whether PKD mediates sustained excitability to proteases. To examine excitability, we made patch clamp recordings from small diameter neurons of mouse dorsal root ganglia.…”

Section: Pkd Mediates Sustained Protease-induced Excitability Ofmentioning

confidence: 99%

See 3 more Smart Citations

Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane

Jensen

Zhao

Jiménez-Vargas

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Agonist-evoked endocytosis of G protein-coupled receptors has been extensively studied. The mechanisms by which agonists stimulate mobilization and plasma membrane translocation of G protein-coupled receptors from intracellular stores are unexplored. Protease-activated receptor-2 (PAR 2 ) traffics to lysosomes, and sustained protease signaling requires mobilization and plasma membrane trafficking of PAR 2 from Golgi stores. We evaluated the contribution of protein kinase D (PKD) and G␤␥ to this process. In HEK293 and KNRK cells, the PAR 2 agonists trypsin and 2-furoyl-LIGRLO-NH 2 activated PKD in the Golgi apparatus, where PKD regulates protein trafficking. PAR 2 activation induced translocation of G␤␥, a PKD activator, to the Golgi apparatus, determined by bioluminescence resonance energy transfer between G␥-Venus and giantin-Rluc8. Inhibitors of PKD (CRT0066101) and G␤␥ (gallein) prevented PAR 2 -stimulated activation of PKD. CRT0066101, PKD1 siRNA, and gallein all inhibited recovery of PAR 2 -evoked Ca 2؉ signaling. PAR 2 with a photoconvertible Kaede tag was expressed in KNRK cells to examine receptor translocation from the Golgi apparatus to the plasma membrane. Irradiation of the Golgi region (405 nm) induced green-red photo-conversion of PAR 2 -Kaede. Trypsin depleted PAR 2 -Kaede from the Golgi apparatus and repleted PAR 2 -Kaede at the plasma membrane. CRT0066101 inhibited PAR 2 -Kaede translocation to the plasma membrane. CRT0066101 also inhibited sustained protease signaling to colonocytes and nociceptive neurons that naturally express PAR 2 and mediate protease-evoked inflammation and nociception. Our results reveal a major role for PKD and G␤␥ in agonist-evoked mobilization of intracellular PAR 2 stores that is required for sustained signaling by extracellular proteases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Pkd Mediates Sustained Protease-induced Excitability Ofmentioning

confidence: 99%

See 2 more Smart Citations

Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane

Jensen

Zhao

Jiménez-Vargas

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Some studies showed no effects on temperature sensation, normal acute responses to noxious heat but impaired inflammatory thermal hyperalgesia while others showed deficits in acute heat responses yet no differences in behavior after inflammation (Liedtke and Friedman 2003; Suzuki and others 2003; Todaka and others 2004; Lee and others 2005; Huang and others 2011). Additionally, inflammatory mediators such as PGE 2 and PAR 2 have been shown to sensitize TRPV4 (Alessandri-Haber and others 2005; Grant and others 2007; Zhao and others 2014). These results indicate that TRPV4 could be required for normal nociception and could have a role in abnormal pain conditions.…”

Section: Trpv4mentioning

confidence: 99%

ThermoTRPs and Pain

Laing

Dhaka

2015

Neuroscientist

View full text Add to dashboard Cite

The ability of the body to perceive noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors. The molecular receptors of noxious mechanical, temperature or chemical stimuli are expressed in these neurons and have drawn considerable attention as possible targets for analgesic development to improve treatment for the millions who suffer from chronic pain conditions. A number of thermoTRPs, a subset of the transient receptor potential family of ion channels, are activated by a wide range on noxious stimuli. In this review, we review the function of these channels and examine the evidence that thermoTRPs play a vital role in acute, inflammatory and neuropathic nociception.

show abstract