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1 Globular Domains Three and Four Induce Heterotrimeric G-Protein binding to -Syntrophin's PDZ Domain and Alter Intracellular Ca2+ in Muscle
1 Deaprtment of Biochemistry, University of Tennessee, Health Science Center, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: hjarrett{at}utmem.edu.
-Syntrophin is a component of the dystrophin glycoprotein complex (DGC). It is firmly attached to the dystrophin cytoskeleton via a unique C-terminal domain and is associated indirectly with -dystroglycan, which binds to extracellular matrix laminin. Syntrophin contains two pleckstrin homology (PH) and one PDZ domain. Since PH domains of other proteins are known to bind the 
subunits of the heterotrimeric G-proteins, whether this is also a property of syntrophin was investigated. Isolated syntrophin from rabbit skeletal muscle binds bovine brain G subunits in gel blot overlay experiments. Laminin-1-Sepharose or specific antibodies against syntrophin, - and -dystroglycan, or dystrophin precipitate a complex with G from crude skeletal muscle microsomes. Bacterially expressed syntrophin fusion proteins and truncation mutants allowed mapping of G-binding to syntrophin's PDZ domain; this is a novel function for PDZ domains. When laminin-1 is bound, maximal binding of Gs and G occurs and active Gs, measured as GTP-35S bound, decreases. Since intracellular Ca2+ is elevated in Duchenne muscular dystrophy and Gs is known to activate the dihydropyridine-receptor Ca2+-channel, whether laminin also altered intacellular Ca2+ was investigated. Laminin-1 decreases active (GTP-S-bound) Gs and the Ca2+-channel is inhibited by laminin-1. The laminin1 chain globular domain 4 and 5 region, the region bound by DGC -dystroglycan, is sufficient to cause effect and an antibody which specifically blocks laminin-binding to -dystroglycan inhibits G-binding by syntrophin in C2C12 myotubes. These observations suggest that the DGC is a matrix laminin, G-protein coupled receptor.
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