Neuregulin-heparan-sulfate proteoglycan interactions produce sustained erbB receptor activation required for the induction of acetylcholine receptorsin muscle

Neuregulins bind to and activate members of the EGF receptor family of tyro sine kinases that initiate a signaling cascade that induces acetylcholine r eceptor synthesis in the postsynaptic membrane of neuromuscular synapses. I n addition to an EGF-like domain, sufficient for receptor binding and tyros ine auto-phosphorylation, many spliced forms also have an IG-like domain th at binds HSPGs and maintains a high concentration of neuregulin at synapses . Here, we show that the IG-like domain functions to keep the EGF-like doma in at sufficiently high concentrations for a sufficiently long period of ti me necessary to induce acetylcholine receptor gene expression in primary ch ick myotubes. Using recombinant neuregulins with and without the IG-like do main, we found that IG-like domain binding to endogenous HSPGs produces a 4 -fold increase in receptor phosphorylation. This enhancement of activity wa s blocked by soluble heparin or by pretreatment of muscle cells with hepari tinase. We show that at least 12-24 h of neuregulin exposure was required t o turn on substantial acetylcholine receptor gene expression and that the e rbB receptors need to be kept phosphorylated during this time. The need for sustained erbB receptor activation may be the reason why neuregulins are s o highly concentrated in the extracellular matrix of synapses.