Mechanism of calcium potentiation of alpha7 nicotinic receptors

Project: Research projectResearch Project

Description

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.
StatusActive
Effective start/end date7/1/166/30/20

Funding

  • National Institutes of Health: $409,976.00

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Nicotinic Receptors
Calcium
Divalent Cations
Cognition Disorders
Drug Design
Barium
Reward
Short-Term Memory
Neurodegenerative Diseases
Cognition
Cholinergic Agents
Schizophrenia
Anti-Inflammatory Agents
Therapeutics
X-Rays
Ions
Ligands
Amino Acids
Brain
Research