? ? 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. ? ? ?
|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|
|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|
|Jansen, Michaela; Rabe, Holger; Strehle, Axelle et al. (2008) Synthesis of GABAA receptor agonists and evaluation of their alpha-subunit selectivity and orientation in the GABA binding site. J Med Chem 51:4430-48|
|Jansen, Michaela; Bali, Moez; Akabas, Myles H (2008) Modular design of Cys-loop ligand-gated ion channels: functional 5-HT3 and GABA rho1 receptors lacking the large cytoplasmic M3M4 loop. J Gen Physiol 131:137-46|