Nerve growth factor (NGF) plays a critical role in the development and growth of sensory neurons. Seminal studies suggest that NGF may also play an important role in the regulating the sensitivity of sensory neurons to noxious stimulation. NGF levels are elevated in inflammatory exudates and is a potent causative agent in the production of both thermal and mechanical hyperalgesia. The behavioral findings suggest that the heightened sensitivity that occurs with inflammation may, in part, result from the actions of NGF on sensory neurons. There have been very few studies exploring the sensitizing actions of NGF on isolated neurons and their associated signaling pathways. Recent work in my laboratory demonstrates that NGF can rapidly augment the excitability of small diameter, capsaicin-sensitive sensory neurons through enhancement of the TTX-resistant sodium current and suppression of a voltage-dependent potassium current(s). Thus, NGF may have a significant impact on the state of neuronal excitability. The notion that NGF may be an important paracrine-type messenger in mediating the excitability of sensory neurons on a rapid time scale, perhaps less than one minute, is a completely unexplored idea.
The Specific Aims outlined in this proposal are:
Aim 1 will determine the effects of NGF on the excitability as well as the modulation of a variety of membrane currents that are critical in setting the firing level of the neuron. These studies will establish whether this sensitization results from activation of Trk A and/or p75 NTR.
Aim 2 will follow an identical course of study to determine whether the other neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3) rapidly modulate the excitability and selected membrane currents. These studies will examine the role of Trk B, Trk C, and/or p75 receptors in modulating excitability.
Aim 3 will establish whether glial cell-derived neurotrophic factor (GDNF) can rapidly modulate selected membrane currents in sensory neurons. GDNF plays a critical role in the growth and survival of a distinct population of non-peptidergic sensory neurons that lose their dependence on NGF.
Aim 4 will explore the intracellular signaling pathways that mediate the rapid modulatory effects of NGF acting through Trk A and p75 NTRs, BDNF and NT-4 through Trk B, NT-3 through Trk C, and GDNF through the Ret kinase pathway. These studies will further our understanding of the cellular mechanisms and signaling pathways whereby neurotrophins acutely regulate the excitability of both nociceptive and non-nociceptive sensory neurons. A fundamental understanding of such events could lead to better designed compounds and therapies to facilitate the treatment of chronic inflammatory conditions. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS046084-01
Application #
6635577
Study Section
Special Emphasis Panel (ZRG1-IFCN-5 (03))
Program Officer
Mamounas, Laura
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$302,125
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Zhang, Y H; Khanna, R; Nicol, G D (2013) Nerve growth factor/p75 neurotrophin receptor-mediated sensitization of rat sensory neurons depends on membrane cholesterol. Neuroscience 248:562-70
Li, Chao; Chi, Xian Xuan; Xie, Wenrui et al. (2012) Sphingosine 1-phosphate receptor 2 antagonist JTE-013 increases the excitability of sensory neurons independently of the receptor. J Neurophysiol 108:1473-83
Zhang, Y H; Kays, J; Hodgdon, K E et al. (2012) Nerve growth factor enhances the excitability of rat sensory neurons through activation of the atypical protein kinase C isoform, PKMýý. J Neurophysiol 107:315-35
Duan, J-H; Wang, Yue; Duarte, D et al. (2011) Ras signaling pathways mediate NGF-induced enhancement of excitability of small-diameter capsaicin-sensitive sensory neurons from wildtype but not Nf1+/- mice. Neurosci Lett 496:70-4
Chi, Xian Xuan; Nicol, G D (2010) The sphingosine 1-phosphate receptor, S1PR?, plays a prominent but not exclusive role in enhancing the excitability of sensory neurons. J Neurophysiol 104:2741-8
Chi, Xian Xuan; Schmutzler, Brian S; Brittain, Joel M et al. (2009) Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons. J Cell Sci 122:4351-62
Zhang, Y H; Chi, Xian Xuan; Nicol, G D (2008) Brain-derived neurotrophic factor enhances the excitability of rat sensory neurons through activation of the p75 neurotrophin receptor and the sphingomyelin pathway. J Physiol 586:3113-27
Zhang, Y H; Vasko, M R; Nicol, G D (2006) Intracellular sphingosine 1-phosphate mediates the increased excitability produced by nerve growth factor in rat sensory neurons. J Physiol 575:101-13
Zhang, Y H; Fehrenbacher, J C; Vasko, M R et al. (2006) Sphingosine-1-phosphate via activation of a G-protein-coupled receptor(s) enhances the excitability of rat sensory neurons. J Neurophysiol 96:1042-52
Wang, Yue; Nicol, G D; Clapp, D Wade et al. (2005) Sensory neurons from Nf1 haploinsufficient mice exhibit increased excitability. J Neurophysiol 94:3670-6

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