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• W2922271788 endingPage "e0213143" @default.
• W2922271788 startingPage "e0213143" @default.
• W2922271788 abstract "Central nervous system nicotinic acetylcholine receptors (nAChR) are predominantly of the α4β2 subtype. Two isoforms exist, with high or low agonist sensitivity (HS-(α4β2)2β2- and LS-(α4β2)2α4-nAChR). Both isoforms exhibit similar macroscopic potency and efficacy values at low acetylcholine (ACh) concentrations, mediated by a common pair of high-affinity α4(+)/(-)β2 subunit binding interfaces. However LS-(α4β2)2α4-nAChR also respond to higher concentrations of ACh, acting at a third α4(+)/(-)α4 subunit interface. To probe isoform functional differences further, HS- and LS-α4β2-nAChR were expressed in Xenopus laevis oocytes and single-channel responses were assessed using cell-attached patch-clamp. In the presence of a low ACh concentration, both isoforms produce low-bursting function. HS-(α4β2)2β2-nAChR exhibit a single conductance state, whereas LS-(α4β2)2α4-nAChR display two distinctive conductance states. A higher ACh concentration did not preferentially recruit either conductance state, but did result in increased LS-(α4β2)2α4-nAChR bursting and reduced closed times. Introduction of an α4(+)/(-)α4-interface loss-of-function α4W182A mutation abolished these changes, confirming this site’s role in mediating LS-(α4β2)2α4-nAChR responses. Small or large amplitude openings are highly-correlated within individual LS-(α4β2)2α4-nAChR bursts, suggesting that they arise from distinct intermediate states, each of which is stabilized by α4(+)/(-)α4 site ACh binding. These findings are consistent with α4(+)/(-)α4 subunit interface occupation resulting in allosteric potentiation of agonist actions at α4(+)/(-)β2 subunit interfaces, rather than independent induction of high conductance channel openings." @default.
• W2922271788 created "2019-03-22" @default.
• W2922271788 creator A5003513677 @default.
• W2922271788 creator A5042951818 @default.
• W2922271788 creator A5045368397 @default.
• W2922271788 creator A5083370387 @default.
• W2922271788 date "2019-03-07" @default.
• W2922271788 modified "2023-09-26" @default.
• W2922271788 title "Distinctive single-channel properties of α4β2-nicotinic acetylcholine receptor isoforms" @default.
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• W2922271788 doi "https://doi.org/10.1371/journal.pone.0213143" @default.
• W2922271788 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6405073" @default.
• W2922271788 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30845161" @default.
• W2922271788 hasPublicationYear "2019" @default.
• W2922271788 type Work @default.
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• W2922271788 hasAuthorship W2922271788A5003513677 @default.
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• W2922271788 hasAuthorship W2922271788A5045368397 @default.
• W2922271788 hasAuthorship W2922271788A5083370387 @default.

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