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  • Title: Synergistic effects of neuregulin and agrin on muscle acetylcholine receptor expression.
    Author: Li Q, Esper RM, Loeb JA.
    Journal: Mol Cell Neurosci; 2004 Aug; 26(4):558-69. PubMed ID: 15276157.
    Abstract:
    The proper function of neuromuscular junctions requires an extremely high density of acetylcholine receptors (AChRs) that may be achieved from neuron-derived factors including agrin and neuregulin. Here, we show that neuregulin-1 and agrin co-localize at neuromuscular junctions in vivo and form complexes when co-transfected into COS-7 cells. When these COS-7 cells are cultured with myotubes, synergistic effects are observed for AChR clustering, membrane insertion of new AChRs, and induction of AChR mRNA. Even a muscle form of agrin that lacks intrinsic clustering activities by itself, significantly enhances neuregulin-induced clustering and insertion of AChRs. While the heparin-binding (A) domain of agrin is required for agrin localization in the extracellular matrix adjacent to AChR clusters, the heparan sulfate-containing domain of agrin is needed for the synergistic effects and co-localization with neuregulin-1. These results suggest that matrix interactions between exogenously supplied agrin and neuregulin-1 on the muscle surface provide a localized source of signaling factors needed to produce high densities of AChRs at neuromuscular junctions.
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