PROJECT SUMMARY- ?7 nicotinic receptors are widely distributed throughout the human brain, and areenriched in regions required for cognition, sensory processing, attention, working memory and reward. Theyhave been implicated in neurodegenerative diseases such as Alzheimer?s and Parkinson?s and psychiatricdiseases such as schizophrenia, and disorders of attention and cognition. ?7 receptors are also present innon-neuronal cells where they contribute to a variety of anti-inflammatory pathways. The overall goal of theproposed research is to develop a mechanistic understanding of activation and modulation of ?7 receptorsapplicable to therapeutic drug design. This proposal will investigate how calcium potentiates ?7 nicotinicreceptors activated by the low agonist concentrations that prevail physiologically. We have developed a co-agonist hypothesis that not only can explain how ?7 signals despite being far from cholinergic nerveterminals, but it also suggests calcium fluctuations associated with neuronal firing regulate ?7 signaling. Toinvestigate calcium potentiation of ?7, X-ray crystallographic methods will be used to determine atomicresolution structures of an ?7 ligand binding domain bound with the potentiating ions calcium and barium. Inparallel, single molecule electrophysiological methods will define the kinetic mechanism behind divalent ionpotentiation. Finally, application of molecular biological and single molecule electrophysiological methods willidentify amino acid residues in ?7 that mediate divalent cation potentiation, and determine the stoichiometrywith which divalent cations potentiate. Completion of this project will reveal mechanistic underpinnings ofactivation and calcium regulation of ?7 applicable to neurological disease treatment and therapeutic drugdesign.
|Effective start/end date||7/1/16 → 6/30/20|
- National Institutes of Health: $409,976.00