Anthony L. Auerbach, PhD.

Anthony L. Auerbach, PhD, studies how functional groups in acetylcholine receptors respond to the neurotransmitter acetylcholine, essential for muscle contraction.

Study Advances Understanding of How Drugs Activate Receptors

Published January 9, 2015 This content is archived.

story based on news release by ellen goldbaum

University at Buffalo research on acetylcholine receptors (AChR) will help pharmacologists better understand how drugs work and could help make “receptor engineering” a reality.

“Once we know the mechanism of exactly how a drug binds a specific molecule, we can engineer the receptor to be able to respond to it more effectively. ”
Anthony L. Auerbach, PhD
Professor of physiology and biophysics

“This research represents a significant advance in our understanding of how drugs activate receptors,” says senior author Anthony L. Auerbach, PhD, professor of physiology and biophysics.

Studying Energy from Drug-Receptor Interactions

Auerbach and his colleagues study how specific functional groups in the AChR respond to acetylcholine and other drugs with similar effects.

The neurotransmitter acetylcholine — when released from the neuron — acts on skeletal muscles to cause them to contract. “We’re taking the ligand-receptor interaction apart and finding out, piece by piece, what makes muscles twitch,” says Auerbach. 

“We have taken this approach down to the level of single side chains and even atoms to understand how a net energy emerges from the interactions between a drug and its receptor.”

Single Amino Acid Affects Potency

Co-author Tapan K. Nayak, PhD, a postdoctoral associate in the Department of Physiology and Biophysics, and colleagues made novel energy measurements from eight different functional groups at three different kinds of neurotransmitter binding sites in fetal- and adult-type AChRs.  

They found that one fetal-type amino acid contributes significantly to the action of acetylcholine and choline, to generate a greater potency.

“The study highlights that — at least in the acetylcholine receptor we studied — sometimes just one specific amino acid, or even one atom, is sufficient to determine potency,” explains Auerbach.

Energy Measurements Key

The key was to measure energy changes that occur when chemicals bind to receptors, notes Auerbach.

“Pharmaceutical industry researchers typically scan large random libraries of candidate molecules,” he says. 

“What we’ve done is strategically pick the whole thing apart down to groups of atoms in the protein, and then predict their dynamic interactions with ligands.”

To the researchers’ knowledge, this is the first time single ligand-binding-site energies have been measured in any receptor.

Findings Could Make ‘Receptor Engineering’ a Reality

The finding may help realize “receptor engineering” — the idea that receptors can be engineered to bind more — or less — potently with natural molecules and drugs.  

“Once we know the mechanism of exactly how a drug binds a specific molecule, we can engineer the receptor to be able to respond to it more effectively,” says Auerbach.

Implications for Escobar Syndrome

The research is relevant to Escobar, or multiple pterygium, syndrome. In this birth-related genetic disease, an essential subunit of the fetal-type AChR malfunctions.

Also, since the transition of fetal-adult AChR is critical for synapse formation, the study will enhance understanding of how cells communicate during development, says Auerbach.

Study Published in PNAS

The study, “Functional Differences Between Neurotransmitter Binding Sites of Muscle Acetylcholine Receptors,” was published in the Proceedings of the National Academy of Sciences.

In addition to Auerbach and Nayak, co-authors are:

  • Iva Bruhova, PhD, and Shaweta Gupta, PhD, postdoctoral associates in the Department of Physiology and Biophysics
  • Srirupa Chakraborty, a doctoral candidate in biophysics 
  • Wenjun Zheng, PhD, associate professor in the Department of Physics

The National Institutes of Health funded the research.