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

J Cell Biol. 2003 Mar 3;160(5):741-52. doi: 10.1083/jcb.200209045. Epub 2003 Feb 25.

Abstract

alpha-Dystrobrevin (DB), a cytoplasmic component of the 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Cytoskeletal Proteins / deficiency*
  • Cytoskeletal Proteins / genetics*
  • Disease Models, Animal
  • Dystrophin-Associated Proteins*
  • Female
  • Immunohistochemistry
  • Male
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Muscle, Skeletal / innervation
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / ultrastructure
  • Muscular Dystrophy, Animal / genetics
  • Muscular Dystrophy, Animal / metabolism
  • Neuromuscular Junction / metabolism*
  • Neuromuscular Junction / ultrastructure
  • Phosphorylation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • Receptors, Cholinergic / metabolism
  • Receptors, Cholinergic / ultrastructure
  • Recombinant Fusion Proteins
  • Sarcolemma / metabolism*
  • Sarcolemma / ultrastructure
  • Synaptic Membranes / genetics
  • Synaptic Membranes / metabolism
  • Tendons / metabolism*
  • Tendons / ultrastructure
  • Tyrosine / metabolism*

Substances

  • Cytoskeletal Proteins
  • Dystrophin-Associated Proteins
  • Membrane Proteins
  • Protein Isoforms
  • Receptors, Cholinergic
  • Recombinant Fusion Proteins
  • dystrobrevin
  • Tyrosine