Capsaicin or vanilloid receptors (VRs) participate in the sensation of thermal and inflammatory pain. The cloned (VR1) and native VRs are non-selective cation channels directly activated by noxious heat, extracellular protons and vanilloid compounds. However, considerable attention has focused on identifying other signaling pathways in VR activation, and this search has gained more significance given the findings that VR1 is expressed in non-sensory tissue and may mediate inflammatory rather than acute thermal pain. Protein kinase C (PKC) plays an important role in pain signaling. Targeted deletion of PKC epsilon in mice dramatically attenuates thermal- and acid-induced hyperalgesia. In turn, activation of PKC epsilon potentiates heat-evoked currents in sensory neurons. Further, the algesic peptide, bradykinin, potentiates heat responses, induces depolarization and evokes secretion from vanilloid-sensitive neurons in a PKC-dependent manner. Yet the molecular targets for these effects have not been clearly identified. In this study we will test the hypothesis that the VR is directly activated by PKC -mediated phosphorylation in the absence of any other agonist. We propose that the pro-inflammatory peptide bradykinin induces VR activity and that this occurs via the stimulation of PKC. We will also test the hypothesis that in the phosphorylated state, a subthreshold stimulus will be sufficient to maximally activate the VR. We propose that phosphorylation of the channel functions as a gain control to modulate the efficacy and sensitivity of VR activation. In this way a range of normally benign stimuli will become potent activators of VRs. This research has important implications for understanding the role of VRs in hyperalgesia, chronic pain and other non-sensory functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042296-04
Application #
6770055
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Porter, Linda L
Project Start
2001-07-15
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2004
Total Cost
$176,250
Indirect Cost
Name
Southern Illinois University School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
038415006
City
Springfield
State
IL
Country
United States
Zip Code
62794
Pabbidi, Mallikarjuna R; Premkumar, Louis S (2017) Role of Transient Receptor Potential Channels Trpv1 and Trpm8 in Diabetic Peripheral Neuropathy. J Diabetes Treat 2017:
Samineni, Vijay K; Premkumar, Louis S; Faingold, Carl L (2017) Neuropathic pain-induced enhancement of spontaneous and pain-evoked neuronal activity in the periaqueductal gray that is attenuated by gabapentin. Pain 158:1241-1253
Cao, De-Shou; Zhong, Linlin; Hsieh, Tsung-Han et al. (2012) Expression of transient receptor potential ankyrin 1 (TRPA1) and its role in insulin release from rat pancreatic beta cells. PLoS One 7:e38005
Samineni, Vijaya Krishna; Premkumar, Louis S; Faingold, Carl L (2011) Post-ictal analgesia in genetically epilepsy-prone rats is induced by audiogenic seizures and involves cannabinoid receptors in the periaqueductal gray. Brain Res 1389:177-82
Premkumar, Louis S (2010) Targeting TRPV1 as an alternative approach to narcotic analgesics to treat chronic pain conditions. AAPS J 12:361-70
Jeffry, Joseph A; Yu, Shuang-Quan; Sikand, Parul et al. (2009) Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia. PLoS One 4:e7021
Walia, Vijay; Ding, Ming; Kumar, Sumit et al. (2009) hCLCA2 Is a p53-Inducible Inhibitor of Breast Cancer Cell Proliferation. Cancer Res 69:6624-32
Sikand, Parul; Premkumar, Louis S (2007) Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse. J Physiol 581:631-47
Premkumar, Louis S; Raisinghani, Manish; Pingle, Sandeep C et al. (2005) Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation. J Neurosci 25:11322-9
Raisinghani, Manish; Pabbidi, Reddy M; Premkumar, Louis S (2005) Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin. J Physiol 567:771-86

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