Central to the mechanisms that underlie central nervous system function and disease are the different neurotransmitter receptors responsible for the rapid signaling between neurons and between nerve and muscle. Like other oligomeric membrane proteins, these neurotransmitter receptor subunits are synthesized and inserted into the membrane of the endoplasmic reticulum (ER) after which the receptor subunits undergo a series of folding and processing steps. The folding and processing steps that occur in the ER transform the individual subunits into mature neurotransmitter receptors before the receptors reach the cell surface. A critical part of the folding and processing that occurs in the ER are the 'quality control' mechanisms that identify, retain and degrade misfolded or misassembled receptor subunits. While much is known about how these receptors function, relatively little is known about how the receptor subunits fold and assemble into functional receptors. The long-term objective of the proposed research is to understand the mechanisms governing the quality control mechanisms in the ER that ensure that only properly assembled and functional receptors are expressed on the cell surface. To achieve this objective, studies will focus on the best-characterized member of this receptor family, the 'muscle-type nicotinic acetyicholine receptor (AChR). The first set of experiments will characterize the interactions between AChR subunits and a specific set of ER resident proteins called chaperone proteins. The second set of experiments will identify the mechanisms involved in the degradation of AChR subunits and determine how subunit degradation affects AChR assembly. The final set of experiments will test whether pathology caused by certain AChR subunit mutations identified in congenital myasthenic syndromes results from defects in AChR assembly or quality control. As the site where nicotine binds in the brain, neuronal AChRs are responsible for nicotine addiction and may play a role in Alzheimer's disease. In addition, the 'muscle-type' AChR is responsible for myasthenia gravis, the autoimmune disease, and many of the congenital myasthenic syndromes both of which cause deterioration of neuromuscular junctions. The level of AChR expression appears to be altered in all three disorders. Since our goal is to elucidate the molecular basis for AChR expression, this proposal should provide insights into certain pathological features of these disorders.
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