Syntrophins are adapter proteins that recruit signaling proteins to the dystrophin complex. Although the dystrophin complex is best known for its role in muscle health (dystrophin mutations cause Duchenne muscular dystrophy), it is now certain that dystrophin-related complexes are important in many different cells, including the central nervous system. In addition to its well-established role in membrane stabilization, this complex is a scaffold for membrane-associated signaling proteins. The syntrophins are key proteins in this signaling function. Five syntrophin isoforms all have a common domain structure. The syntrophin PDZ domain binds signaling proteins (nNOS and several kinases) and channels (potassium and sodium channels and aquaporin-4). Gene-targeted mice lacking a-syntrophin do not express nNOS and aquaporin-4 on the sarcolemma, and also are deficient in utrophin at the neuromuscular synapse, a-syntrophin null mice also have a brain phenotype. Because aquaporin-4 is absent from its proper location in perivascular astrocytic endfeet, a-syntrophin null mice are resistant to brain edema and the infarct volume following ischemia is substantially smaller. The goal of this application is to understand the molecular mechanisms of syntrophin-ligand regulation and to apply this knowledge to in vivo function. We will determine the mechanisms by which the interaction of syntrophins with the dystrophin family and with signaling proteins is regulated. The role of PH domain interaction with phosphatidylinositol lipids in targeting utrophin to the sarcolemma will be determined. The importance of post-translational modifications, such as phosphorylation, will be studied in muscle and astrocytes. Linker proteins that may mediate interaction between the a-syntrophin PDZ domain and aquaporin-4 will be identified. Finally, based on results from DNA chip array experiments that compared gene expression in normal and a-syntrophin null muscle, we will examine the role of a-syntrophin in the expression and localization of the epsilon subunit of the nicotinic receptor, two potassium channels and the transient receptor channel, TRPC 1. These results will expand our understanding of the regulation of signaling proteins by syntrophins and may reveal new therapeutic targets for the treatment of muscular dystrophy, epilepsy, and brain edema following stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033145-12
Application #
7071044
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Porter, John D
Project Start
1995-04-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
12
Fiscal Year
2006
Total Cost
$342,337
Indirect Cost
Name
University of Washington
Department
Physiology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Fuhrmann-Stroissnigg, Heike; Noiges, Rainer; Descovich, Luise et al. (2012) The light chains of microtubule-associated proteins MAP1A and MAP1B interact with ýý1-syntrophin in the central and peripheral nervous system. PLoS One 7:e49722
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