Tyrosine-phosphorylated and nonphosphorylated isoforms of α-dystrobrevin:: roles in skeletal muscle and its neuromuscular and myotendinous junctions

被引:79
作者
Grady, RM
Akaaboune, M
Cohen, AL
Maimone, MM
Lichtman, JW
Sanes, JR
机构
[1] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA
[3] SUNY Upstate Med Univ, Dept Cell & Dev Biol, Syracuse, NY 13210 USA
关键词
dystrobrevin; dystrophin; muscular dystrophy; myotendinous junction; neuromuscular junction;
D O I
10.1083/jcb.200209045
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
alpha-Dystrobrevin (DB), a cytoplasmic component of the L-dystrophin-glycoprotein complex, is found throughout the sarcolemma of muscle cells. Mice lacking alphaDB exhibit muscular dystrophy, defects in maturation of neuromuscular junctions (NMJs) and, as shown here, abnormal myotendinous junctions (MTJs). In normal muscle, alternative splicing produces two main alphaDB isoforms, alphaDB1 and alphaDB2, with common NH2-terminal but distinct COOH-terminal domains. alphaDB1, whose COOH-terminal extension can be tyrosine phosphorylated, is concentrated at the NMJs and MTJs. alphaDB2, which is not tyrosine phosphorylated, is the predominant isoform in extrajunctional regions, and is also present at NMJs and MTJs. Transgenic expression of either isoform in alphaDB(-/-) mice prevented muscle fiber degeneration; however, only alphaDB1 completely corrected defects at the NMJs (abnormal acetylcholine receptor patterning, rapid turnover, and low density) and MTJs (shortened junctional folds). Site-directed mutagenesis revealed that the effectiveness of alphaDB1 in stabilizing the NMJ depends in part on its ability to serve as a tyrosine kinase substrate. Thus, alphaDB1 phosphorylation may be a key regulatory point for synaptic remodeling. More generally, alphaDB may play multiple roles in muscle by means of differential distribution of isoforms with distinct signaling or structural properties.
引用
收藏
页码:741 / 752
页数:12
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