Abstract
The extent to which agonists activate synaptic receptor-channels depends on both the intrinsic tendency of the unliganded receptor to open and the amount of agonist binding energy realized in the channel-opening process. We examined mutations of the nicotinic acetylcholine receptor transmitter binding site (α subunit loop B) with regard to both of these parameters. αGly147 is an “activation” hinge where backbone flexibility maintains high values for intrinsic gating, the affinity of the resting conformation for agonists and net ligand binding energy. αGly153 is a “deactivation” hinge that maintains low values for these parameters. αTrp149 (between these two glycines) serves mainly to provide ligand binding energy for gating. We propose that a concerted motion of the two glycine hinges (plus other structural elements at the binding site) positions αTrp149 so that it provides physiologically optimal binding and gating function at the nerve-muscle synapse.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS064969].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.068767.
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ABBREVIATIONS:
- AChR
- nicotinic acetylcholine receptor
- ACh
- acetylcholine
- R
- resting-closed AChRs
- R*
- active-open state AChRs
- PBS
- phosphate-buffered saline
- wt
- wild type
- Po
- open probability
- R/E
- rate-equilibrium
- Cho
- choline.
- Received September 7, 2010.
- Accepted November 29, 2010.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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