Neurons are highly polarized cells and require the sequestration of ion channels, as well another components, in specific locations. Within myelinated axons, voltage -dependant Na+ channels are clustered and anchored at initial segments and nodes of Ranvier, and this organization is essential for both the integration of information and the rapid propagation of action potentials overlong distances. The project seeks to understand the mechanisms involved in achieving and maintaining this distribution. This work is important both during development of the nervous system, and also in several disease states, including multiple sclerosis and Guillain-Barre Syndrome. This research seeks first to distinguish between two very different hypotheses for the neuron-glial interactions that are responsible for Na+ channel clustering. Are sites of high channel density determined solely by the axon, or are they induced by myelinating glia? Further, is a destabilization of the cytoskeleton the immediate cause of Na+ channel diffusion to these sites? We have recently found that contactin, a surface protein with homology to one of the auxiliary subunits of the Na+ channel, can increase expression of this channel several-fold in-transfected cells. We seek now to characterize the molecular basis for this regulation, and to investigate the function of contactin in neurons and glia. This will be done through mutational analysis, biochemical association assays, and functional measurements. The ultimate aim is to understand how critical neuronal components are regulated and distributed to insure reliable signaling. This information will then be helpful in designing therapies for diseases of the brain, spinal cord, and periphery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS017965-18
Application #
6639367
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Utz, Ursula
Project Start
1981-12-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
18
Fiscal Year
2003
Total Cost
$377,330
Indirect Cost
Name
University of Rochester
Department
Neurosciences
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Feinberg, Konstantin; Eshed-Eisenbach, Yael; Frechter, Shahar et al. (2010) A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier. Neuron 65:490-502
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