Ligand-gated ion channels
Neuronal nicotinic receptor assembly and expression
Nicotinic acetylcholine receptors are ligand-gated ion channels, a large family of multimeric membrane-bound proteins that open an ionic channel when the appropriate agonist binds.
Multiple subunits for nicotinic acetylcholine receptors exist in neurons, and different combinations of subunits can assemble into many different functional receptor subtypes.
A major thrust of my laboratory is to determine the composition and function of neuronal nicotinic receptor subtypes and what regulates their expression in neuronal tissues.
Extended exposure to nicotinic agonists causes increased surface expression (up-regulation) of many nicotinic receptor subtypes, a phenomenon that has been implicated in the addictive property of nicotine.
We are examining the mechanism of up-regulation by using surface-labeling and molecular biological methods. In addition, the alpha7 nicotinic receptor protein is heterologously expressed in almost all cell types in culture but only folds and forms a functional receptor in very few.
We are investigating the role of cell-line dependent factors such as Ric3 on alpha7 receptor assembly and expression. Also, nicotinic receptors signal using other pathways besides acting as ligand gated ion channels. We are investigating how nicotinic receptors affect STAT3 and NFkB signaling in nicotine-mediated anti-inflammatory effects.
Moaddel R, Sharma A, Huseni T, Jones GS, Jr., Hanson RN, Loring RH. Novel biotinylated phenyl-arsonous acids as bifunctional reagents for spatially close thiols: studies on reduced antibodies and the agonist binding site of reduced Torpedo nicotinic receptors. Bioconjug Chem 10:629-37 (1999).
Sweileh W., Wenberg K., Xu J., Forsayeth J., Hardy S., and Loring, R.H. Multistep Expression and Assembly of Neuronal Nicotinic Receptors is Both Host-Cell and Receptor-Subtype Dependent. Mol. Brain Res., 75:293-302 (2000).
S. Goklany, R.H. Loring, J. Glick, C. W.T. Lee-Parsons. Assessing the limitations to terpenoid indole alkaloid biosynthesis in Catheranthus roseus hairy root cultures through gene expression profiling and precursor feeding. Biotechnology Progress, 25:1289-96 (2009).
V. Hosur, S. Leppanen, A. Abutaha, and R.H. Loring. Gene regulation of α4β2 nicotinic receptors: Microarray analysis of nicotine-induced α4β2 up-regulation and anti-inflammatory effects. Journal of Neurochemistry, 111: 848-58, (2009).
V. Hosur and R.H. Loring. α4β2 Nicotinic Receptors Partially Mediate Anti-Inflammatory Effects through Janus Kinase 2 (JAK2) – Signal Transducer and Activator of Transcription 3 (STAT3) but Not Calcium or cAMP Signaling. Molecular Pharmacology 79:167-74. (2011).