Protein Kinase D Isoforms Are Expressed in Rat and Mouse Primary Sensory Neurons and Are Activated by Agonists of Protease-Activated Receptor 2

Silvia Amadesi, Andrew D. Grant, Graeme S. Cottrell, Natalya Vaksman, Daniel P. Poole, Enrique Rengurt, Nigel W. Bunnett

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


Serine proteases generated during injury and inflammation cleave protease-activated receptor 2 (PAR(2)) on primary sensory neurons to induce neurogenic inflammation and hyperalgesia. Hyperalgesia requires sensitization of transient receptor potential vanilloid (TRPV) ion channels by mechanisms involving phospholipase C and protein kinase C (PKC). The protein kinase D (PKD) serine/threonine kinases are activated by diacylglycerol and PKCs and can phosphorylate TRPV1. Thus, PKDs may participate in novel signal transduction pathways triggered by serine proteases during inflammation and pain. However, it is not known whether PAR2 activates PKD, and the expression of PKD isoforms by nociceptive neurons is poorly characterized. By using HEK293 cells transfected with PKDs, we found that PAR2 stimulation promoted plasma membrane translocation and phosphorylation of PKD1, PKD2, and PKD3, indicating activation. This effect was partially dependent on PKC epsilon. By immunofluorescence and confocal microscopy, with antibodies against PKD1/PKD2 and PKD3 and neuronal markers, we found that PKDs were expressed in rat and mouse dorsal root ganglia (DRG) neurons, including nociceptive neurons that expressed TRPV1, PAR(2), and neuropeptides. PAR(2) agonist induced phosphorylation of PKD in cultured DRG neurons, indicating PKD activation. In-traplantar injection of PAR(2) agonist also caused phosphorylation of PKD in neurons of lumbar DRG, confirming activation in vivo. Thus, PKD1, PKD2, and PKD3 are expressed in primary sensory neurons that mediate neurogenic inflammation and pain transmission, and PAR(2) agonists activate PKDs in HEK293 cells and DRG neurons in culture and in intact animals. PKD may be a novel component of a signal transduction pathway for protease-induced activation of nociceptive neurons and an important new target for anti-inflammatory and analgesic therapies. J. Comp. Neurol. 516: 141-156, 2009. (C) 2009 Wiley-Liss, Inc.
Original languageEnglish
Pages (from-to)141 - 156
Number of pages16
JournalJournal of Comparative Neurology
Issue number2
Publication statusPublished - 10 Sept 2009


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