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Laminin-α 1 Globular Domains Three and Four Induce Heterotrimeric G-Protein Binding to α-Syntrophin ’ s PDZ Domain and Alter Intracellular Ca 2 + in Muscle

α-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 α-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 βγ subunits of the heterotrimeric Gproteins, whether this is also a property of syntrophin was investigated. Isolated syntrophin from rabbit skeletal muscle binds bovine brain Gβγ subunits in gel blot overlay experiments. Laminin-1-Sepharose or specific antibodies against syntrophin, αand β-dystroglycan, or dystrophin precipitate a complex with Gβγ from crude skeletal muscle microsomes. Bacterially expressed syntrophin fusion proteins and truncation mutants allowed mapping of Gβγ−binding to syntrophin's PDZ domain; this is a novel function for PDZ domains. When laminin-1 is bound, maximal binding of Gsα and Gβγ occurs and active Gsα, measured as GTP-γS bound, decreases. Since intracellular Ca is elevated in Duchenne muscular dystrophy and Gsα is known to activate the dihydropyridine-receptor Ca-channel, whether laminin also altered intacellular Ca2+ was investigated. Laminin-1 decreases active (GTP-γS-bound) Gsα and the Cachannel is inhibited by laminin-1. The laminin α1 chain globular domain 4 and 5 region, the region bound by DGC α-dystroglycan, is sufficient to cause effect and an antibody which specifically blocks laminin-binding to α-dystroglycan inhibits Gβ-binding by syntrophin in C2C12 myotubes. These observations suggest that the DGC is a matrix laminin, G-protein coupled receptor.