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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-2 (01))
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Utz, Ursula
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University of Rochester
Schools of Dentistry
United States
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Einheber, Steven; Meng, Xiaosong; Rubin, Marina et al. (2013) The 4.1B cytoskeletal protein regulates the domain organization and sheath thickness of myelinated axons. Glia 61:240-53
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