Previous electrophysiological and pharmacological analysis of K channels in mammalian myelinated nerves have established that dysregulation of K channels underlie major conduction deficits in demyelinating diseases. However, neither the molecular specificity of the K channel genes involved nor the molecular mechanism for their proper membrane localization are known. The long-term goal is to fill in this knowledge gap. The immediate goal is to focus on Kv1.1, a fast delayed rectifier that is expressed specifically at the paranodal junction and is co-regulated with myelin genes. We will utilize a Kv1.1 null mutant mouse generated in our laboratory to explore three important questions concerning this K channel that are relevant to our understanding of abnormal functions in demyelinating diseases. For the first time, myelinated nerves with normal morphology but with a K channel subtype genetically deleted underneath the myelin is available for functional analysis.
In Aim 1, we will use the Kv1.1 null mutant to explore a novel role played by Kv1.1 in stabilizing transition zones and branch points in myelinated fibers.
In Aim 2, we will utilize our Kv1.1 null mutant to examine whether Kv1.1 is the key potassium channel responsible for conduction block, or for promoting survival of, demyelinated axons.
In Aim 3, we will use our Kv1.1 null mutant as a null background against which transgenes can be introduced to test two hypotheses of channel clustering. Relatedly, the role of Kvbeta subunits, which colocalize with Kv1.1 and are thought to promote efficient surface expression, will be examined in Kvbeta mutant mice (also generated in our laboratory).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023375-18
Application #
6682696
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (03))
Program Officer
Utz, Ursula
Project Start
1986-04-01
Project End
2006-11-30
Budget Start
2003-12-01
Budget End
2006-11-30
Support Year
18
Fiscal Year
2004
Total Cost
$363,876
Indirect Cost
Name
University of Wisconsin Madison
Department
Physiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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