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Published on: August 16, 2018
Acetylcholine receptor channels activated by a single agonist molecule
Archana Jha1, Anthony Auerbach
1Department of Physiology and Biophysics, State University of New York, Buffalo, New York, USA.
Biophysical Journal
|May 6, 2010
Summary
Researchers studied the neuromuscular acetylcholine receptor (AChR), an allosteric protein, to understand how agonists trigger its gating isomerization. They found that even with one binding site, agonists like ACh can effectively gate the receptor, providing insights into its function.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- The neuromuscular acetylcholine receptor (AChR) is a critical allosteric protein mediating signal transmission at the neuromuscular junction.
- AChR cycles between inactive (R) and active (R) conformations, with the R state exhibiting higher agonist affinity and ionic conductance.
- Understanding the mechanism by which agonists induce the R to R gating isomerization is crucial for comprehending synaptic transmission.
Purpose of the Study:
- To investigate how agonists trigger the gating isomerization of the neuromuscular acetylcholine receptor (AChR).
- To analyze single-channel currents from adult mouse muscle AChRs engineered to have only one functional agonist binding site.
- To determine the monoliganded gating equilibrium constant (E(1)) and quantify the energy changes associated with agonist binding and receptor gating.
Main Methods:
- Examined single-channel currents from adult mouse muscle AChRs with a single functional agonist binding site.
- Utilized electrophysiological techniques to record receptor activity and analyze gating kinetics.
- Estimated the monoliganded gating equilibrium constant (E(1)) and energy changes for different agonists.
Main Results:
- AChRs with a single operational binding site exhibited a single population of currents, suggesting symmetrical agonist affinity for the two binding sites.
- The monoliganded gating equilibrium constant (E(1)) was determined to be approximately 4.3 x 10(-3) for ACh and 1.7 x 10(-4) for choline.
- The unliganded AChR gating constant (E(0)) was estimated at approximately 6.5 x 10(-7), with gating altering ligand-protein complex stability by 5.2 kcal/mol (ACh) and 3.3 kcal/mol (choline).
Conclusions:
- Agonist binding energy can effectively drive the gating isomerization of the neuromuscular acetylcholine receptor, even with only one binding site engaged.
- The study provides quantitative estimates for gating equilibrium constants and energy changes, elucidating the allosteric mechanism of AChR activation.
- Findings contribute to a deeper understanding of the structure-function relationship and activation dynamics of nicotinic acetylcholine receptors.
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