Neuronal plasticity arises from the regulation of gene expression by plasma membrane excitation. In cells undergoing """"""""plastic"""""""" changes a signaling pathway must exist which couples the membrane to macromolecular synthesis. We plan to study this pathway (or pathways), whose molecular details are not known, in the vertebrate skeletal muscle fiber, a simple model system that displays activity-controlled modulation of protein composition. Because of the magnitude and speed of the response, the acetylcholine receptor synthesis rate is selected as an indicator of """"""""plastic"""""""" change. We will attempt to establish the level (transcriptional vs. post-transcriptional) at which receptor synthesis is regulated by measuring concentrations of receptor mRNA and correlating them with observed rates of receptor subunit synthesis, assembly and appearance in the plasma membrane. These studies will be carried out with adult chicken muscle under conditions of denervation and reinnervation (which lead to dramatic increases and decreases, respectively, of receptor synthesis rate), and with cultured chick embryo myotubes, which modulate their acetylcholine receptor output in response to various chemical and pharmacological stimuli. Initially, the investigation will be restricted to the -subunit of the receptor because all required molecular tools are already available for this peptide chain. Subsequently, similar analyses will be carried out on the remaining polypeptide components. Eventually we hope to identify the second messenger involved in control of receptor synthesis and to provide a complete description of how muscle membrane activity and receptor expression are coupled.
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