Email this pagePrincipal Investigator
Research Projects
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How are sodium channels clustered at nodes of Ranvier?
Prior to myelination (and following demyelination) sodium channels are present throughout the axon membrane at low density. A former graduate student, Jin Wu, characterized these and other axonal channels with patch clamp measurements. When glial cells (Schwann cells in the peripheral nervous system) adhere to axons and begin myelination, sodium channels rapidly cluster adjacent to the tips of the glial processes that are extended during early stages of ensheathment. More info...
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Ion channels are distributed at specific sites in neurons
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. More info...
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Neuronal polarity during development
Early in neuronal development, neurites become polarized into dendrites and the axon. One fundamental event involves the targeting of sodium channels to the initial segment of the axon, a site that may function as the zone of action potential initiation. In the figure above a motor neuron has been cultured from embryonic spinal cord. After 4 days in vitro the cell was labeled with antibodies against neurofilaments (red) and sodium channels (green). Only one neurite, destined to be the axon, has the cluster of sodium channels. In contrast with the situation at nodes of Ranvier, this channel clustering occurs independently of glial cells. Our laboratory is interested in the mechanisms by which neurites become polarized, and in particular, how ion channels are targeted to specific processes. We are also studying the electrophysiological consequences of the 10-30 micron region of the axon that is devoid of sodium channels and could serve to limit excitability. These spinal motor neurons are further of considerable interest since they are primary targets of the disease process in amyotrophic lateral sclerosis. More info...
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The role of voltage-dependent potassium channels in myelinated axons
Voltage-dependent potassium channels have a reciprocal relationship with sodium channels, and are located primarily in clusters several micrometers on either side of the node, as seen in the top figure. We have shown that axonal potassium channels play important roles during both early development and in disease. Over the first few postnatal days, Shaker-type potassium channels stabilize conduction and prevent repetitive firing. In disease, following demyelination the juxtaparanodal potassium channel clusters break up. When remyelination begins, these channels cluster first within the nodal gap, and impede the restoration of function. One aspect of our work involves a search for pharmacological agents that act with high specificity on these potassium channels to improve conduction in several disease states More info...
Recent Publications
- (2009 Mar 05). Early events in node of Ranvier formation during myelination and remyelination in the PNS. Neuron Glia Biol. 2, 69-79.
- (2008 Mar 13). Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength. J Neurosci. 28, 2753-65.
- (2007 Aug 28). Neurofascin assembles a specialized extracellular matrix at the axon initial segment. J Cell Biol. 178, 875-86.
