This research project aims at studying the muscle nicotinic acetylcholine receptor (nAChR) structure and the conformational changes it undergoes during channel activation. Nicotinic AChR mediate fast synaptic transmission at the nerve-muscle junction and in the brain. The recent publication of the ACh binding protein (AChBP) and Torpedo AChR structures has allowed new insights into the three dimensional structure and provides the basis for the following Specific Aims: 1) To test the validity of the 4-A resolution AChR transmembrane domain model by determining proximity relationships between specific transmembrane segment residues. 2) To determine the thermal mobility of the M2 channel-lining segments in the resting and activated states. 3) To map structural changes in the transmembrane domain during activation. 4) To probe protein packing around the M2-M3 loop that is involved in the transduction of ligand binding to channel gating. The results will validate the structural information inferred from the 4-A resolution data. In addition they will be used to refine the structural model of the receptor. This will allow more detailed investigations of binding sites for allosteric ligands, thus allowing design of Improved drugs, in addition, this study will elucidate dynamic events such as thermal and gating-induced movements.
Acetylcholine receptors have been implicated in diseases such as Alzheimer's and Parkinson's disease, attention deficit hyperactivity disorder, depression, schizophrenia, myasthenia gravis and nicotine dependence. This study aims at Investigating the molecular basis of AChR structure and function as a prerequisite for understanding the mechanisms by which current clinically used drugs act and for finding Improved treatments fnr these disorders.
