Actions of GTPase-Activating Proteins on Sensory Neurons

Indiana University Indianapolis, Indianapolis IN

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Abstract

The activity of sensory neurons can be modulated to elicit enhanced responsiveness;a phenomenon known as peripheral sensitization. This is a major component of the hypersensitivity produced in inflammation and may contribute to chronic pain syndromes. Although growth factors and inflammatory cytokines are clearly sensitizers of sensory neurons, many of the cellular mechanisms by which these compounds modify the function of sensory neurons remain unclear. Better understanding of these mechanisms is critical to understanding the etiology of inflammatory pain and developing better therapies for the treatment of chronic pain states. Both nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF) initiate signalling through the Ras transduction cascade and so this pathway may be important in the development of peripheral sensitization. The activity of this cascade is regulated by GTPase activating protiens (GAPs), such as neurofibromin and SynGAP. Despite the growing evidence to suggest that Ras-GTP initiated signaling pathways are important in the sensitization of sensory neurons and the key role of GAPs in regulating the initiation of these cascades, there has been no work to determine the importance of GAPs in peripheral sensitization. We hypothesize that the GAPs, SynGAP and neurofibromin, can modulate the sensitivity of sensory neurons. We will alter GAP expression in adult mouse primary sensory neurons grown in culture and measure changes in the excitability and stimulated release of neuropeptide transmitters in the presence and absence of NGF and GDNF treatment. In addition, we will determine if mice with reduction of SynGAP or neurofibromin exhibit altered response to noxious thermal or mechanical stimulation as a behavioral indication of peripheral sensitization. Finally, we will begin to examine whether the actions of GAPs on sensory neuron function are mediated through increased activity of the MAPK or PI-3K pathways.