A fundamental principle of biomedicine is that drugs bind to proteins to influence their output and, hence, cell physiology. The overall goal of our experiments is to understand the mechanisms by which ligands bind to neuromuscular acetylcholine receptors, and how this event influences the probability that these membrane proteins allow ions to cross the cell membrane. These receptors are molecular machines that reversibly couple the energy of ligand binding to that for the mechanical work of a global conformational change. Our objective is to reveal the moving parts of the binding site apparatus, and to measure the energy changes associated with each part. By doing so we will understand, design and control how this receptor responds to drugs. This knowledge can be applied to closely-related receptors that are common targets for drugs (both therapeutic and of abuse) and play roles in behavior and diseases of the nervous system.

Public Health Relevance

The experiments will establish the fundamental principles for engineering drugs to bind to receptors and cause them to change their functional output. A model system will be used to make the measurements, and the knowledge gained will be applied to a broad class of receptors important in human health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064969-08
Application #
9063633
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Silberberg, Shai D
Project Start
2009-04-01
Project End
2019-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Physiology
Type
Schools of Medicine
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228
Nayak, Tapan K; Auerbach, Anthony (2017) Cyclic activation of endplate acetylcholine receptors. Proc Natl Acad Sci U S A 114:11914-11919
Gupta, Shaweta; Chakraborty, Srirupa; Vij, Ridhima et al. (2017) A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip. J Gen Physiol 149:85-103
Bruhova, Iva; Auerbach, Anthony (2017) Molecular recognition at cholinergic synapses: acetylcholine versus choline. J Physiol 595:1253-1261
Nayak, Tapan Kumar; Chakraborty, Srirupa; Zheng, Wenjun et al. (2016) Structural correlates of affinity in fetal versus adult endplate nicotinic receptors. Nat Commun 7:11352
Auerbach, Anthony (2016) Dose-Response Analysis When There Is a Correlation between Affinity and Efficacy. Mol Pharmacol 89:297-302
Vij, Ridhima; Purohit, Prasad; Auerbach, Anthony (2015) Modal affinities of endplate acetylcholine receptors caused by loop C mutations. J Gen Physiol 146:375-86
Auerbach, Anthony (2015) Activation of endplate nicotinic acetylcholine receptors by agonists. Biochem Pharmacol 97:601-608
Purohit, Prasad; Chakraborty, Srirupa; Auerbach, Anthony (2015) Function of the M1 ?-helix in endplate receptor activation and desensitization. J Physiol 593:2851-66
Auerbach, Anthony (2015) Agonist activation of a nicotinic acetylcholine receptor. Neuropharmacology 96:150-6
Purohit, Prasad; Bruhova, Iva; Gupta, Shaweta et al. (2014) Catch-and-hold activation of muscle acetylcholine receptors having transmitter binding site mutations. Biophys J 107:88-99

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