Nitric oxide is a downstream mediator of agrin-induced acetylcholine receptor aggregation

The synaptic basal lamina protein, agrin, is required for the formation of the neuromuscular junction. Agrin signals through a muscle-specific recepto r tyrosine kinase (MuSK) initiating a cascade of events that lead to the ag gregation of acetylcholine receptors (ACI IR) at the postsynaptic site. Ano ther important synaptic signalling molecule is nitric oxide (NO), which is produced by the enzyme, nitric oxide synthase (NOS). We investigated the in teraction between the agrin signalling cascade and the NO signalling cascad e by treating cultured myotubes with agrin, NOS inhibitors, and NO donors. NOS inhibitors prevented agrin induced AChR aggregation and phosphorylation of the AChR beta subunit. Furthermore, NO donors induced AChR aggregation in the absence of agrin, as well as phosphorylation of the AChR beta subuni t. These results demonstrate a role for NO as a downstream mediator of agri n induced AChR aggregation and AChR beta subunit phosphorylation at the neu romuscular junction.