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.

National Institute of Health (NIH)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Silberberg, Shai D
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State University of New York at Buffalo
Schools of Medicine
United States
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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
Poulin, Hugo; Bruhova, Iva; Timour, Quadiri et al. (2014) Fluoxetine blocks Nav1.5 channels via a mechanism similar to that of class 1 antiarrhythmics. Mol Pharmacol 86:378-89
Purohit, Prasad; Auerbach, Anthony (2013) Loop C and the mechanism of acetylcholine receptor-channel gating. J Gen Physiol 141:467-78
Gupta, Shaweta; Purohit, Prasad; Auerbach, Anthony (2013) Function of interfacial prolines at the transmitter-binding sites of the neuromuscular acetylcholine receptor. J Biol Chem 288:12667-79
Jadey, Snehal; Purohit, Prasad; Auerbach, Anthony (2013) Action of nicotine and analogs on acetylcholine receptors having mutations of transmitter-binding site residue ýýG153. J Gen Physiol 141:95-104
Auerbach, Anthony (2013) The energy and work of a ligand-gated ion channel. J Mol Biol 425:1461-75
Nayak, Tapan K; Auerbach, Anthony (2013) Asymmetric transmitter binding sites of fetal muscle acetylcholine receptors shape their synaptic response. Proc Natl Acad Sci U S A 110:13654-9
Bruhova, Iva; Gregg, Timothy; Auerbach, Anthony (2013) Energy for wild-type acetylcholine receptor channel gating from different choline derivatives. Biophys J 104:565-74
Auerbach, Anthony (2012) Thinking in cycles: MWC is a good model for acetylcholine receptor-channels. J Physiol 590:93-8

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