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The Journal of Neuroscience, November 17, 2004, 24(46):10302-10309; doi:10.1523/JNEUROSCI.3408-04.2004

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Cellular/Molecular
Structural Abnormalities at Neuromuscular Synapses Lacking Multiple Syntrophin Isoforms

Marvin E. Adams,¹ Neal Kramarcy,² Taku Fukuda,³ Andrew G. Engel,³ Robert Sealock,² and Stanley C. Froehner¹

¹Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195, ²Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, and ³Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905

The syntrophins are modular adapter proteins that function by recruiting signaling molecules to the cytoskeleton via their direct association with proteins of the dystrophin protein family. We investigated the physiological function of 2-syntrophin by generating a line of mice lacking this syntrophin isoform. The 2-syntrophin null mice show no overt phenotype, or muscular dystrophy, and form structurally normal neuromuscular junctions (NMJs). To determine whether physiological consequences caused by the lack of 2-syntrophin were masked by compensation from the -syntrophin isoform, we crossed these mice with our previously described -syntrophin null mice to produce mice lacking both isoforms. The /2-syntrophin null mice have NMJs that are structurally more aberrant than those lacking only -syntrophin. The NMJs of the /2-syntrophin null mice have fewer junctional folds than either parent strain, and the remaining folds are abnormally shaped with few openings to the synaptic space. The levels of acetylcholine receptors are reduced to 23% of wild type in mice lacking both syntrophin isoforms. Furthermore, the /2-syntrophin null mice ran significantly shorter distances on voluntary exercise wheels despite having normal neuromuscular junction transmission as determined by micro-electrode recording of endplate potentials. We conclude that both -syntrophin and 2-syntrophin play distinct roles in forming and maintaining NMJ structure and that each syntrophin can partially compensate for the loss of the other.

Key words: dystrophin; acetylcholine receptor; nNOS; junctional folds; scaffold; neuromuscular

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Received Aug 18, 2004; revised October 1, 2004; accepted October 5, 2004.

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