Syntrophins are modular adapter proteins, whose importance can be inferred from their association with dystrophin, the product of the Duchenne and Becker muscular dystrophy gene. In skeletal muscle, dystrophin is associated with a complex of transmembrane glycoproteins and peripheral membrane proteins that link the extracellular matrix to cytoskeletal actin. A multitude of muscle pathologies results from mutations in proteins of the dystrophin complex. All syntrophins, of which four are now known, have a characteristic domain structure: two pleckstrin homology (PH) domains, a PDZ domain and a domain unique to syntrophin (SU domain. We have shown that the tandem PH2SU domain binds to dystrophin and that syntrophin PDZ domains bind ion channels (sodium channels, certain potassium channels) and neuronal nitric oxide synthase (nNOS), thereby linking them to the dystrophin complex. In this application, we will test the hypothesis that syntrophins confer a membrane signaling function on the dystrophin complex and that the syntrophin PDZ domains are especially important. We will use biochemical and molecular biological methods to identify additional syntrophin binding proteins, including ones that associate via non-PDZ interactions. The importance of syntrophin in the association of syntrophin with agrin-induced acetylcholine receptor clusters will be examined in cultured myotubes. To examine the function of syntrophin interactions with skeletal muscle ion channels, we have developed genetically-altered mice lacking alpha- and b2-syntrophin. We now propose to study the effects of syntrophin deficiency on acetylcholine receptor clustering and on sodium channel distribution and physiology. Finally, the importance of syntrophins in muscle pathology will be examined. We will compare muscle abnormalities in the genetically-altered mice with mdx mouse and determine if muscle activity (in the form of exercise) exacerbates degeneration. These studies are expected to expand our understanding of the syntrophin complex as an organizing center for transmembrane signaling proteins and define the role of syntrophins in the complex. A role for syntrophin abnormalities in human muscle pathologies may also be revealed.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-MDCN-1 (01))
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Spinella, Giovanna M
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University of Washington
Schools of Medicine
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Nanou, Evanthia; Yan, Jin; Whitehead, Nicholas P et al. (2016) Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels. Proc Natl Acad Sci U S A 113:1068-73
Allen, David G; Whitehead, Nicholas P; Froehner, Stanley C (2016) Absence of Dystrophin Disrupts Skeletal Muscle Signaling: Roles of Ca2+, Reactive Oxygen Species, and Nitric Oxide in the Development of Muscular Dystrophy. Physiol Rev 96:253-305
Froehner, Stanley C; Reed, Sarah M; Anderson, Kendra N et al. (2015) Loss of nNOS inhibits compensatory muscle hypertrophy and exacerbates inflammation and eccentric contraction-induced damage in mdx mice. Hum Mol Genet 24:492-505
Hebel, Tobias; Eisinger, Kristina; Neumeier, Markus et al. (2015) Lipid abnormalities in alpha/beta2-syntrophin null mice are independent from ABCA1. Biochim Biophys Acta 1851:527-36
Eisinger, Kristina; Froehner, Stanley C; Adams, Marvin E et al. (2015) Evaluation of the specificity of four commercially available antibodies to alpha-syntrophin. Anal Biochem 484:99-101
Neumeier, Markus; Krautbauer, Sabrina; Schmidhofer, Sandra et al. (2013) Adiponectin receptor 1 C-terminus interacts with PDZ-domain proteins such as syntrophins. Exp Mol Pathol 95:180-6
Cruz, Nancy F; Ball, Kelly K; Froehner, Stanley C et al. (2013) Regional registration of [6-(14)C]glucose metabolism during brain activation of ?-syntrophin knockout mice. J Neurochem 125:247-59
Eilert-Olsen, Martine; Haj-Yasein, Nadia Nabil; Vindedal, Gry Fluge et al. (2012) Deletion of aquaporin-4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier. Glia 60:432-40
Johnson, Eric K; Zhang, Liwen; Adams, Marvin E et al. (2012) Proteomic analysis reveals new cardiac-specific dystrophin-associated proteins. PLoS One 7:e43515
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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