The gating isomerization of neuromuscular acetylcholine receptors
Acetylcholine receptor-channels are allosteric proteins that isomerize (âgate') 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 in | The Journal of physiology Vol. 588; no. 4; pp. 573 - 586 |
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Main Author | |
Format | Journal Article |
Language | English |
Published |
Oxford, UK
The Physiological Society
15.02.2010
Blackwell Publishing Ltd Wiley Subscription Services, Inc Blackwell Science Inc |
Subjects | |
Online Access | Get full text |
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Summary: | Acetylcholine receptor-channels are allosteric proteins that isomerize (âgate') 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 â 6.5 Ã 10 â7 . At each (equivalent) transmitter binding site acetylcholine provides â¼5.2 kcal mol â1 to motivate the isomerization. The partial agonist choline provides â¼3.3 kcal mol â1 . The relative time of a residue's gating energy change is revealed by the slope of its rateâequilibrium 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. |
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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 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Feature-3 ObjectType-Review-1 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 |