We have identified a new synaptic specialization at the neuromuscular junction. It consists of a steady, or d.c. electric current, focused precisely at the nerve-muscle synapse. We have characterized the physiological mechanism by which the current is generated. In the next grant period, we will focus on the biological role of the current, that is, the function it serves in the life of the cell. Possible roles include the guidance of neurite growth and the electrophoretic movement of intracellular molecules important for synaptic function. We will disrupt the current chronically in rats, and search for altered nerve-muscle function and structure. In a second study, we will characterize skeletal muscle membrane chloride transport properties, focusing on two pumping mechanisms identified in other cell types. These mechanisms are chloride-bicarbonate exchange, and sodium-chloride cotransport. Since chloride transport abnormalities have been implicated in several clinical diseases, including cystic fibrosis and muscular dystrophy, these studies may be important in understanding the etiology of these diseases. In a third study, we will test the hypothesis that intracellular chloride is important in governing the expression of acetylcholine receptors in the muscle fiber membrane. Preliminary results suggest that elevation of internal chloride concentration may provide the """"""""trigger"""""""" for synthesis and insertion into the membrane of acetylcholine receptors. If the hypothesis is confirmed, an important gap in our understanding of this best understood animal membrane protein will be filled.
