Date of Award

3-27-2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Patrick Carr

Abstract

SSeCKS (src suppressed C kinase substrate) is an A kinase anchoring protein that has been localized in the peripheral and central nervous systems. Previous studies have suggested that SSeCKS is restricted to a population of small-diameter neurons in the dorsal root ganglia whose central axons terminate in superficial laminae of the spinal cord dorsal horn. This SSeCKS containing population displayed labeling characteristics consistent with non-peptidergic C-fibers and occasionally contained nerve growth factor receptors. The present study investigated the hypothesis that SSeCKS is found in a subgroup of primary sensory neurons that are involved in transmission of nociceptive stimuli. This was implemented through molecular and morphological characterization of SSeCKS labeled primary sensory neurons at the light microscopic level, analysis of SSeCKS labeling in the spinal cord dorsal horn at the ultrastructural level, examination of SSeCKS plasticity in animal models of nociception, and analysis of SSeCKS labeling and function in cell culture. The results demonstrated that SSeCKS is predominantly localized to C-fibers (85%), but also a small proportion (15%) of an A-delta variety, that are capable of conveying cutaneous nociceptive stimuli. In addition to the occasional incidence of NGF receptors reported previously, SSeCKS was shown to share colocalization properties with the GDNF α-2 receptor (22%), suggesting that the SSeCKS containing population is sensitive to both NGF and GDNF. Furthermore, analysis of SSeCKS in pain models suggests that SSeCKS may display molecular plasticity in response to various painful stimuli, particularly following complete Freund's adjuvant (CFA) administration and sciatic nerve ligature. Cell cultural SSeCKS analysis indicates that SSeCKS may undergo redistribution in response to PKA and PKC activation as well as calcium influx, suggesting that SSeCKS may be regulated dynamically in an intracellular signaling pathway. Although SSeCKS could not be linked to a specific receptor-mediated intracellular signaling cascade, it is possible that SSeCKS may play an intricate role in compartmentalizing intracellular nociceptive signaling cascades. These results indicate that SSeCKS may be involved in nociceptive transmission and its involvement in PKA/PKC modulated nociceptive hypersensitivity remains to be determined.

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