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.
|Labriola, Jonathan M; Pandhare, Akash; Jansen, Michaela et al. (2013) Structural sensitivity of a prokaryotic pentameric ligand-gated ion channel to its membrane environment. J Biol Chem 288:11294-303|
|Mnatsakanyan, Nelli; Jansen, Michaela (2013) Experimental determination of the vertical alignment between the second and third transmembrane segments of muscle nicotinic acetylcholine receptors. J Neurochem 125:843-54|
|Goyal, Raman; Salahudeen, Ahmed Abdullah; Jansen, Michaela (2011) Engineering a prokaryotic Cys-loop receptor with a third functional domain. J Biol Chem 286:34635-42|
|Wiltfong, Roger Ernest; Jansen, Michaela (2009) Probing protein packing surrounding the residues in and flanking the nicotinic acetylcholine receptor M2M3 loop. J Neurosci 29:1626-35|
|Bali, Moez; Jansen, Michaela; Akabas, Myles H (2009) GABA-induced intersubunit conformational movement in the GABAA receptor alpha 1M1-beta 2M3 transmembrane subunit interface: experimental basis for homology modeling of an intravenous anesthetic binding site. J Neurosci 29:3083-92|