A long-term goal of my research is to characterize mechanisms of neuroplasticity associated with tissue injury and chronic pain. My previous studies have demonstrated that the sensitization of nociceptive neurons in trigeminal subnucleus caudalis (Vc), which underlies allodynia and hyperalgesia in the orofacial region, results from the up-regulation of the N-methyl-D-aspartate (NMDA) type glutamate receptor. Recently, we have shown that NMDA receptor activity is regulated by a receptor-associated protein tyrosine kinase-phosphatase complex, which consists of Src family protein tyrosine kinases (PTKs), the Src family PTK activator (protein tyrosine phosphatase alpha (PTPalpha)) and inhibitor (C-terminal Src kinase (Csk)). In this complex, Src family PTKs are principal effectors regulating NMDA channel activity. PTPalpha acts as an endogenous driver for the initiation and maintenance of Src family PTK activity necessary for the constitutive regulation of NMDA receptors while Csk inactivates Src family PTKs and thereby down-regulates NMDA receptors. To date, PTPalpha remains the only phosphatase found to be actively involved in the induction of long-term potentiation (LTP) of excitatory synaptic functions in the central nervous system. Based on these findings I hypothesize that the NMDA receptor-associated PTPalpha-Src-Csk protein complex may play very important roles in the regulation of transducing noxious stimuli in the orofacial region into nociceptive signals in Vc. To examine this hypothesis, I propose to investigate how the PTPalpha-Src-Csk protein complex regulates 1) glutamate-mediated basal synaptic responses in Vc nociceptive neurons, 2) A- and C-fiber input-induced synaptic responses in Vc neurons, 3) the synaptic functions of Vc neurons in animals where the majority of C-afferent fiber innervations is removed. No such studies have yet been conducted in Vc, and so the proposed research promises to reveal novel molecular networks involved in the regulation of orofacial pain. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS053567-01
Application #
6895697
Study Section
Special Emphasis Panel (ZDE1-PW (04))
Program Officer
Porter, Linda L
Project Start
2005-06-15
Project End
2009-05-31
Budget Start
2005-06-15
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$292,000
Indirect Cost
Name
Florida State University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
790877419
City
Tallahassee
State
FL
Country
United States
Zip Code
32306
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Xie, Yu-Feng; Pflueger, Melissa; Feng, Shuang et al. (2012) Locally released small (non-protein) ninhydrin-reacting molecules underlie developmental differences of cultured medullary versus spinal dorsal horn neurons. J Neurochem 122:605-18
Groveman, Bradley R; Feng, Shuang; Fang, Xiao-Qian et al. (2012) The regulation of N-methyl-D-aspartate receptors by Src kinase. FEBS J 279:20-8
Feng, Shuang; Pflueger, Melissa; Lin, Shuang-Xiu et al. (2012) Regulation of voltage-gated sodium current by endogenous Src family kinases in cochlear spiral ganglion neurons in culture. Pflugers Arch 463:571-84
Fang, Xiao-Qian; Xu, Jindong; Feng, Shuang et al. (2011) The NMDA receptor NR1 subunit is critically involved in the regulation of NMDA receptor activity by C-terminal Src kinase (Csk). Neurochem Res 36:319-26
Groveman, Bradley R; Xue, Sheng; Marin, Vedrana et al. (2011) Roles of the SH2 and SH3 domains in the regulation of neuronal Src kinase functions. FEBS J 278:643-53
Marin, Vedrana; Groveman, Bradley R; Qiao, Haifa et al. (2010) Characterization of neuronal Src kinase purified from a bacterial expression system. Protein Expr Purif 74:289-97
Yu, Xian-Min; Groveman, Bradley R; Fang, Xiao-Qian et al. (2010) THE ROLE OF INTRACELLULAR SODIUM (Na) IN THE REGULATION OF CALCIUM (Ca)-MEDIATED SIGNALING AND TOXICITY. Health (Irvine Calif) 2:8-15
Xu, Jindong; Weerapura, Manjula; Ali, Mohammad K et al. (2008) Control of excitatory synaptic transmission by C-terminal Src kinase. J Biol Chem 283:17503-14