In:
American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 288, No. 2 ( 2005-02), p. C377-C388
Kurzfassung:
α-Syntrophin is a component of the dystrophin glycoprotein complex (DGC). It is firmly attached to the dystrophin cytoskeleton via a unique COOH-terminal domain and is associated indirectly with α-dystroglycan, which binds to extracellular matrix laminin. Syntrophin contains two pleckstrin homology (PH) domains and one PDZ domain. Because PH domains of other proteins are known to bind the βγ-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 Gβγ-subunits in gel blot overlay experiments. Laminin-1-Sepharose or specific antibodies against syntrophin, α- and 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 G s α and Gβγ occurs and active G s α, measured as GTP-γ 35 S bound, decreases. Because intracellular Ca 2+ is elevated in Duchenne muscular dystrophy and G s α is known to activate the dihydropyridine receptor Ca 2+ channel, whether laminin also altered intracellular Ca 2+ was investigated. Laminin-1 decreases active (GTP-γS-bound) G s α, and the Ca 2+ channel is inhibited by laminin-1. The laminin α 1 -chain globular domains 4 and 5 region, the region bound by DGC α-dystroglycan, is sufficient to cause an effect, and an antibody that specifically blocks laminin binding to α-dystroglycan inhibits Gβ binding by syntrophin in C 2 C 12 myotubes. These observations suggest that DGC is a matrix laminin, G protein-coupled receptor.
Materialart:
Online-Ressource
ISSN:
0363-6143
,
1522-1563
DOI:
10.1152/ajpcell.00279.2004
Sprache:
Englisch
Verlag:
American Physiological Society
Publikationsdatum:
2005
ZDB Id:
1477334-X
SSG:
12
