The neuromuscular junction is highly specialized, containing high concentrations of several cytoskeletal, membrane, and extracellular matrix components that are virtually absent from extrasynaptic portions of the muscle fiber surface. The best studied of these synapse-specific proteins is the acetylcholine receptor (AChR). AChRs are present throughout the membrane of embryonic myotubes, but become concentrated at synapses and are lost from extrasynaptic areas after synapses form. However, denervation or paralysis of adult muscle induces synthesis and insertion of new AChRs in extrasynaptic areas. We have begun to study the mechanisms of regulation of AChR levels in developing, normal adult and denervated adult muscle. Using cloned cDNA probes for AChR subunits we have shown that AChR mRNA levels are: 1) maximal in terminally differentiated muscle cell cultures; 2) increased 100 fold within 3 days following denervation of adult muscle; and 3) highly concentrated near synaptic regions in normal innervated adult fibers. These results suggest that a unique mechanism operating at the transcriptional level could be involved in the specific regulation of AChRs at the neuromuscular junction. The unique aspect of this regulation would be that muscle activity inhibits AChR gene expression in extrasynaptic nuclei, whereas expression of AChR genes in synaptic nuclei is maintained at high levels. Thus, synaptic and extrasynaptic nuclei within a single fiber's cytoplasm might differ in their patterns of gene expression. Such a mechanism might be shared by and, therefore, result in the co-regulation of a diverse family of genes for synapse specific proteins other than AChR's, such as components of the basal lamina and subsynaptic cytoskeletal proteins. The specific regulation of synaptic components could be common to neurons by the peripheral and central nervous systems.
