Agrin-independent activation of the agrin signal transduction pathway

The neural factor agrin induces the aggregation of acetylcholine receptors (AChRs) and other synaptic molecules on cultured myotubes, This aggregating activity can be mimicked by experimental manipulations that include treatm ent with neuraminidase or elevated calcium. We report evidence that neurami nidase and calcium act through the agrin signal transduction pathway. The e ffects of neuraminidase and calcium on AChR clustering are additive with th at of agrin at low concentrations and cosaturating at high concentrations. In addition, like agrin, both neuraminidase and calcium cause rapid tyrosin e phosphorylation of the muscle-specific kinase (MuSK) and the AChR-beta su bunit, Our results argue that all three agents act directly on components o f the same signal transduction complex, We suggest that sialic acids on com ponents of the complex inhibit interactions necessary for signal transducti on and that disinhibition can result in activation. In such a model, agrin could activate signal transduction by disinhibition or by circumventing the inhibition. (C) 1999 John Wiley & Sons, Inc. J Neurobiol 40: 356-365, 1999 .