Nicotinic Acetylcholine Receptor Structure, Thermal Motion and Gating

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DESCRIPTION (provided by applicant): Dr. Michaela Jansen is a postdoctoral fellow in the lab of Dr. Myles Akabas. Her long term career goals are to obtain an independent faculty position performing research in the field of molecular physiology and pharmacology of ion channels and transporters. Her immediate career goals are to develop an independent research program that will form the basis for beginning an independent scientific career. To accomplish this she will obtain independent funding and increase her fundamental knowledge of ion channels and membrane transport and related issues of protein structure-function, bioinformatics and molecular modeling. To increase her repertoire of experimental techniques she will learn to perform patch clamp recording and single channel analysis, molecular modeling and membrane protein biochemistry. This will be accomplished in the context of a research project to study the muscle nicotinic acetylcholine receptor (AChR) 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 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 elucidate dynamic events such as thermal and gating-induced movements. AChR have been implicated in a variety of neurological diseases such as Alzheimer's and Parkinson's disease, Attention deficit hyperactivity disorder, depression, schizophrenia, myasthenia gravis and in nicotine dependence. Understanding the molecular basis of AChR function is a prerequisite for finding improved treatments for these disorders. Our results will provide valuable tools for understanding how disease causing mutations interfere with function, how drugs used clinically modulate function, and also a basis to design new drugs.