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Protein kinase D isoforms are expressed in rat and mouse primary sensory neurons and are activated by agonists of protease-activated receptor 2.
J Comp Neurol. 2009 Sep 10; 516(2):141-56.JC

Abstract

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 PAR(2) activates PKD, and the expression of PKD isoforms by nociceptive neurons is poorly characterized. By using HEK293 cells transfected with PKDs, we found that PAR(2) stimulation promoted plasma membrane translocation and phosphorylation of PKD1, PKD2, and PKD3, indicating activation. This effect was partially dependent on PKCepsilon. 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. Intraplantar 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 antiinflammatory and analgesic therapies.

Authors+Show Affiliations

Center for Neurobiology of Digestive Diseases, University of California, San Francisco, San Francisco, California 94143-0660, USA.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, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19575452

Citation

Amadesi, Silvia, et al. "Protein Kinase D Isoforms Are Expressed in Rat and Mouse Primary Sensory Neurons and Are Activated By Agonists of Protease-activated Receptor 2." The Journal of Comparative Neurology, vol. 516, no. 2, 2009, pp. 141-56.
Amadesi S, Grant AD, Cottrell GS, et al. Protein kinase D isoforms are expressed in rat and mouse primary sensory neurons and are activated by agonists of protease-activated receptor 2. J Comp Neurol. 2009;516(2):141-56.
Amadesi, S., Grant, A. D., Cottrell, G. S., Vaksman, N., Poole, D. P., Rozengurt, E., & Bunnett, N. W. (2009). Protein kinase D isoforms are expressed in rat and mouse primary sensory neurons and are activated by agonists of protease-activated receptor 2. The Journal of Comparative Neurology, 516(2), 141-56. https://doi.org/10.1002/cne.22104
Amadesi S, et al. Protein Kinase D Isoforms Are Expressed in Rat and Mouse Primary Sensory Neurons and Are Activated By Agonists of Protease-activated Receptor 2. J Comp Neurol. 2009 Sep 10;516(2):141-56. PubMed PMID: 19575452.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein kinase D isoforms are expressed in rat and mouse primary sensory neurons and are activated by agonists of protease-activated receptor 2. AU - Amadesi,Silvia, AU - Grant,Andrew D, AU - Cottrell,Graeme S, AU - Vaksman,Natalya, AU - Poole,Daniel P, AU - Rozengurt,Enrique, AU - Bunnett,Nigel W, PY - 2009/7/4/entrez PY - 2009/7/4/pubmed PY - 2009/9/25/medline SP - 141 EP - 56 JF - The Journal of comparative neurology JO - J Comp Neurol VL - 516 IS - 2 N2 - 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 PAR(2) activates PKD, and the expression of PKD isoforms by nociceptive neurons is poorly characterized. By using HEK293 cells transfected with PKDs, we found that PAR(2) stimulation promoted plasma membrane translocation and phosphorylation of PKD1, PKD2, and PKD3, indicating activation. This effect was partially dependent on PKCepsilon. 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. Intraplantar 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 antiinflammatory and analgesic therapies. SN - 1096-9861 UR - https://www.unboundmedicine.com/medline/citation/19575452/Protein_kinase_D_isoforms_are_expressed_in_rat_and_mouse_primary_sensory_neurons_and_are_activated_by_agonists_of_protease_activated_receptor_2_ L2 - https://doi.org/10.1002/cne.22104 DB - PRIME DP - Unbound Medicine ER -