Publication Date:
2009-04-03
Description:
In the course of synaptic transmission in the brain and periphery, acetylcholine receptors (AChRs) rapidly transduce a chemical signal into an electrical impulse. The speed of transduction is facilitated by rapid ACh association and dissociation, suggesting a binding site relatively non-selective for small cations. Selective transduction has been thought to originate from the ability of ACh, over that of other organic cations, to trigger the subsequent channel-opening step. However, transitions to and from the open state were shown to be similar for agonists with widely different efficacies. By studying mutant AChRs, we show here that the ultimate closed-to-open transition is agonist-independent and preceded by two primed closed states; the first primed state elicits brief openings, whereas the second elicits long-lived openings. Long-lived openings and the associated primed state are detected in the absence and presence of an agonist, and exhibit the same kinetic signatures under both conditions. By covalently locking the agonist-binding sites in the bound conformation, we find that each site initiates a priming step. Thus, a change in binding-site conformation primes the AChR for channel opening in a process that enables selective activation by ACh while maximizing the speed and efficiency of the biological response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712348/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712348/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mukhtasimova, Nuriya -- Lee, Won Yong -- Wang, Hai-Long -- Sine, Steven M -- NS031744/NS/NINDS NIH HHS/ -- R01 NS031744/NS/NINDS NIH HHS/ -- R01 NS031744-18/NS/NINDS NIH HHS/ -- England -- Nature. 2009 May 21;459(7245):451-4. doi: 10.1038/nature07923. Epub 2009 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19339970" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line
;
Disulfides/metabolism
;
Electric Conductivity
;
Humans
;
Kinetics
;
Models, Molecular
;
*Movement
;
Nicotinic Agonists/pharmacology
;
Patch-Clamp Techniques
;
Protein Structure, Tertiary
;
Receptors, Nicotinic/*chemistry/genetics/*metabolism
;
Synaptic Transmission/physiology
;
Torpedo
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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