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.
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