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Department of Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545
The syntrophins are a multigene family of intracellular dystrophin-associated proteins comprising
three isoforms, The sarcolemmal distribution of
1,
1, and
2. Based on their domain
organization and association with neuronal nitric oxide
synthase, syntrophins are thought to function as modular adapters that recruit signaling proteins to the membrane via association with the dystrophin complex. Using sequences derived from a new mouse
1-syntrophin
cDNA, and previously isolated cDNAs for
1- and
2-syntrophins, we prepared isoform-specific antibodies to
study the expression, skeletal muscle localization, and
dystrophin family association of all three syntrophins.
Most tissues express multiple syntrophin isoforms. In
mouse gastrocnemius skeletal muscle,
1- and
1-syntrophin are concentrated at the neuromuscular junction
but are also present on the extrasynaptic sarcolemma.
1-syntrophin is restricted to fast-twitch muscle fibers,
the first fibers to degenerate in Duchenne muscular
dystrophy.
2-syntrophin is largely restricted to the
neuromuscular junction.
1- and
1-syntrophins suggests association with dystrophin and dystrobrevin, whereas all three syntrophins could potentially
associate with utrophin at the neuromuscular junction.
Utrophin complexes immunoisolated from skeletal
muscle are highly enriched in
1- and
2-syntrophins, while dystrophin complexes contain mostly
1- and
1-syntrophins. Dystrobrevin complexes contain dystrophin and
1- and
1-syntrophins. From these results,
we propose a model in which a dystrophin-dystrobrevin complex is associated with two syntrophins. Since
individual syntrophins do not have intrinsic binding
specificity for dystrophin, dystrobrevin, or utrophin, the
observed preferential pairing of syntrophins must depend on extrinsic regulatory mechanisms.
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