The gating isomerization of neuromuscular acetylcholine receptors

Acetylcholine receptor-channels are allosteric proteins that isomerize (‘gate') between conformations that have a low vs. high affinity for the transmitter and conductance for ions. In order to comprehend the mechanism by which the affinity and conductance changes are linked it is of value to...

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Published inThe Journal of physiology Vol. 588; no. 4; pp. 573 - 586
Main Author Auerbach, Anthony
Format Journal Article
LanguageEnglish
Published Oxford, UK The Physiological Society 15.02.2010
Blackwell Publishing Ltd
Wiley Subscription Services, Inc
Blackwell Science Inc
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Summary:Acetylcholine receptor-channels are allosteric proteins that isomerize (‘gate') between conformations that have a low vs. high affinity for the transmitter and conductance for ions. In order to comprehend the mechanism by which the affinity and conductance changes are linked it is of value to know the magnitude, timing and distribution of energy flowing through the system. Knowing both the di- and unliganded gating equilibrium constants ( E 2 and E 0 ) is a foundation for understanding the AChR gating mechanism and for engineering both the ligand and the protein to operate in predictable ways. In adult mouse neuromuscular receptors activated by acetylcholine, E 2 = 28 and E 0 ≈ 6.5 × 10 −7 . At each (equivalent) transmitter binding site acetylcholine provides ∼5.2 kcal mol −1 to motivate the isomerization. The partial agonist choline provides ∼3.3 kcal mol −1 . The relative time of a residue's gating energy change is revealed by the slope of its rate–equilibrium constant relationship. A map of this parameter suggests that energy propagates as a conformational cascade between the transmitter binding sites and the gate region. Although gating energy changes are widespread throughout the protein, some residues are particularly sensitive to perturbations. Several specific proposals for the structural events that comprise the gating conformational cascade are discussed.
Bibliography:The Journal of Physiology
This report was presented at
which took place at the Society for Neuroscience meeting in Chicago, on 16 October 2009. It was commissioned by the Editorial Board and reflects the views of the author.
Symposium on
Advances and hold‐ups in the study of structure, function and regulation of Cys‐loop ligand‐gated ion channels and receptors
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This report was presented at The Journal of Physiology Symposium on Advances and hold-ups in the study of structure, function and regulation of Cys-loop ligand-gated ion channels and receptors, which took place at the Society for Neuroscience meeting in Chicago, on 16 October 2009. It was commissioned by the Editorial Board and reflects the views of the author.
ISSN:0022-3751
1469-7793
DOI:10.1113/jphysiol.2009.182774