The goal of this research is to understand the physiological role of the family of nicotinic acetylcholine receptor genes that has been discovered in the mammalian genome. One set of genes codes for the nicotinic acetylcholine receptors that are present at the neuromuscular junction in skeletal muscle. This receptor is the target of the autoimnune response in the disease myasthenia gravis. Recombinant DNA techniques will be used to locate the region of the receptor that is the main site of attack by the immune system. The relationship between the structure of the acetylcholine receptor and the function of the receptor will be elucidated by means of site specific mutagenesis. The promoter regions of the receptor will be studied in order to understand how electrical activity regulates gene expression. A molecular genetic approach has led to the discovery of a set of genes coding for nicotinic acetylcholine receptors expressed in the peripheral and central nervous system. The products of these genes may code for the nicotinic receptors found in the brain. Although not a prescribed drug, smoking has created a large population of addicts that are exposed to nicotine over long periods. This addition, which has enormous health costs may be mediated by this receptor family. There is some evidence that Alzheimer's disease involves, as one of its symptoms, a deficient in the nicotinic receptor system in the brain. The structure, regulation and function of this receptor family will be studied in order to understand the role that these receptors play in the normal and diseased brain. Recombinant DNA techniques including the production of transgenic mice, as well as electrophysiological methods will be used for these studies. The nicotinic acetylcholine receptors are phosphorylated and there is evidence that phosphorylation alters the properties or the functional state of the receptor. Site specific mutation will be used to determine whether phosphorylation of the receptor changes the properties of the synapse. The pharmacology of the brain nicotinic system will be studied in the oocyte expression system using voltage clamp and patch clamp techniques.
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