Inappropriate expression of nicotinic acetylcholine receptors in the central nervous system is associated with nicotine addiction, Alzheimer’s disease, Parkinson’s disease and other disorders. Modulators (drugs) have the potential to restore circuit properties that arise from inappropriate expression of nicotinic receptor’s. Compounds that interact with allosteric sites have a distinct advantage over agonists and partial agonists, in that, they retain normal activation patterns by allowing binding of the endogenous ligand. Positive allosteric modulators boost the receptors ability to respond to agonist. Studies of these modulators constitute a first step toward the identification and development of better compounds that minimize signaling errors at cholinergic synapses. We have used single molecule methods to investigate the action of a novel positive allosteric modulator, desformylflustrabromine (dFBr), on nicotinic receptors. Our studies were focused on the α4β2 subtype of nicotinic receptors in the brain. These receptors exist in two forms with low sensitivity (α42β23) or, alternatively, high sensitivity (α42β23) to agonist. Our experiments allowed us to develop detailed gating models for high and low sensitivity receptors, as well as gain new insights regarding the mechanisms that underlie potentiation by allosteric modulators. We found that dFBr potentiates low sensitivity receptors by destabilizing desensitized states of the receptor. In contrast, potentiation of high sensitivity receptors arises from a synchronization of openings following an application of agonist due to an increase in the opening rate. Based on our results we now have a better understanding of the advantages of dFBr on high and low sensitivity receptors.
|Commitee:||Dunlap, Kriya, Kuhn, Thomas, Schulte, Marvin|
|School:||University of Alaska Fairbanks|
|Department:||Chemistry & Biochemistry|
|School Location:||United States -- Alaska|
|Source:||DAI-B 78/05(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Pharmacy sciences, Biophysics|
|Keywords:||Allosteric modulators, Alzheimer's disease, Desformylflustrabromine, Nicotine addiction, Nicotinic acetylcholine, Single-channel|
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