Maintenance of Acetylcholine Receptor Number by Neuregulins at the Neuromuscular Junction in Vivo

TLDR

Neuregulin family protein ARIA, found at motor endplates, indicates that neuregulins mediate nerve-dependent accumulation of acetylcholine receptors in the postsynaptic membrane. Synaptic analysis in neuregulin-deficient mice examined the role of these proteins at the neuromuscular junction. Heterozygous deletion of Ig-domain neuregulin isoforms produced myasthenia, reduced postsynaptic AChR density (lower mEPP amplitude and bungarotoxin binding), yet preserved evoked potentials through increased quanta release, demonstrating lifelong dependence of AChR density on Ig-containing neuregulins.

Abstract

ARIA (for acetylcholine receptor–inducing activity), a protein purified on the basis of its ability to stimulate acetylcholine receptor (AChR) synthesis in cultured myotubes, is a member of the neuregulin family and is present at motor endplates. This suggests an important role for neuregulins in mediating the nerve-dependent accumulation of AChRs in the postsynaptic membrane. Nerve-muscle synapses have now been analyzed in neuregulin-deficient animals. Mice that are heterozygous for the deletion of neuregulin isoforms containing an immunoglobulin-like domain are myasthenic. Postsynaptic AChR density is significantly reduced, as judged by the decrease in the mean amplitude of spontaneous miniature endplate potentials and bungarotoxin binding. On the other hand, the mean amplitude of evoked endplate potentials was not decreased, due to an increase in the number of quanta released per impulse, a compensation that has been observed in other myasthenic states. Thus, the density of AChRs in the postsynaptic membrane depends on immunoglobulin-containing neuregulin isoforms throughout the life of the animal.