Principal Investigator

Peter Shrager, Ph.D. University of Rochester work Box 603 601 Elmwood Ave Rochester NY 14642 office: MC 4-5428 p 585-275-4748

Ion channels are distributed at specific sites in neurons

A node of Ranvier from an axon in the sciatic nerve, and sodium channels appear green; potassium channels (Kv1.2), blue, and caspr (a protein that serves as a paranodal junction between the myelinating glial cell and the axon), red.

Neurons are highly polarized cells, and their proper functioning depends on specific targeting of membrane proteins, including ion channels, to appropriate regions. For example, voltage-dependent sodium channels must be localized at high density at the initial segment of the axon, and must also be clustered at nodes of Ranvier. The initial segment is the site at which synaptic inputs are integrated and the action potential is initiated. The nodes of Ranvier are gaps in the insulating myelin, and constitute regions where the impulse is regenerated for propagation down the axon. Within these zones, ion channels and other key proteins are clustered in a highly specific manner. This can be seen in the accompanying figure, in which antibodies targeted against individual components have been applied and made visible with fluorescent tags.

In the above node, it is clear from the lack of overlap, that these 3 proteins are actively sequestered in a very specific manner. Successful conduction depends on a complex interaction between neurons and their associated myelinating glial cells to create both the myelin itself, and the required ion channel distribution. In our laboratory, this system is studied in both development and disease. At birth axons have little myelin, but by the end of the first postnatal week in the PNS (and second week in the CNS) both glial ensheathment and ion channel clustering are at an advanced state. In multiple sclerosis myelin is damaged, and ion channel distributions are disrupted. The immune mechanisms responsible for this pathology are not known. We study the molecular mechanisms responsible for these phenomena using electrophysiology, immunocytochemistry, molecular biology, and transgenic manipulations, and we are interested in both the structural distributions and the functional consequences of channel organization.

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