Molecular mechanisms of activation of ion channels
Research Synopsis:
Our research is focused on the molecular mechanisms of activation of neuronal nicotinic acetylcholine receptors. These receptors are essential for normal synaptic activity in the brain. They are the target for nicotine, so they are an important component in nicotine addiction. Abnormalities of cholinergic neurotransmission are important in Alzheimer’s disease, schizophrenia, epilepsy, and other neurological disorders.
We are testing the hypothesis that ligand-driven conformational changes during activation include both subunit rotation and intrasubunit movements of a specific beta-sheet. To characterize these conformational changes, we use cysteine mutagenesis, analysis of chemical modification rates, and electrophysiological approaches to characterize the functional properties of cloned receptors. We use a molecular model of the ligand-binding domain of the receptors to guide our mutagenesis and to help us interpret the results.
Recent Publications:
McLaughlin, J.T., Fu, J., and Rosenberg, R.L. (2007) Agonist-driven conformational changes in the inner beta-sheet of alpha7 nicotinic receptors. Mol Pharmacol 71(5): 1312-1318. Abstract
McLaughlin, J.T., Fu, J., Sproul, A.D., and Rosenberg, R.L. (2006) Role of the Outer {beta} Sheet in Divalent Cation Modulation of {alpha}7 Nicotinic Receptors. Molecular Pharmacology. Mol Pharmacol 70(1): 16-22. Abstract
Olesky, M., Zhao, S., Rosenberg, R.L., and Nicholas, R.A. (2006) Porin-mediated antibiotic resistance in Neisseria gonorrhoeae: Ion, solute, and antibiotic permeation through PIB proteins with penB mutations. J Bacteriol 188(7): 2300-8. Abstract
Lyford, L.K., Sproul A.D., Eddins, D., McLaughlin, J.T., and Rosenberg, R.L. (2003) Agonist-dependent conformational changes in the extracellular domain of a 7 nicotinic ACh receptors. Mol Pharmacol 64(3): 650-658. Abstract
Eddins, D.E., Sproul, A.D., Lyford, L.K., McLaughlin, J.T., and Rosenberg, R.L. (2002) Glutamate 172, essential for modulation of L 247 T a 7 ACh receptors by Ca 2+, lines the extracellular vestibule. Am J Physiol (Cell Physiol) 283(5): C1454-C1460. Abstract
Lyford, L.K., Lee, J.W., and Rosenberg, R.L. (2002) Low affinity Ca 2+ and Ba 2+ binding sites in the pore of a 7 nicotinic acetylcholine receptors. Biochim. Biophys. Acta 1559(1): 69-78. Abstract
Eddins, D., Lyford, L.K., Desai, S.A., and Rosenberg , R.L. (2002) Permeant but not impermeant divalent cations enhance the activation of non-desensitizing a 7 nicotinic receptors. Am J Physiol (Cell Physiol) 282(4): C796-C804. Abstract
