Department
neurobiology
Document Type
Article
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) 2 β2- and LS-(α4β2) 2 α4-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) 2 α4-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) 2 β2-nAChR exhibit a single conductance state, whereas LS-(α4β2) 2 α4-nAChR display two distinctive conductance states. A higher ACh concentration did not preferentially recruit either conductance state, but did result in increased LS-(α4β2) 2 α4-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) 2 α4-nAChR responses. Small or large amplitude openings are highly-correlated within individual LS-(α4β2) 2 α4-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.
Publication Date
3-1-2019
Publication Title
PLoS ONE
ISSN
19326203
Volume
14
Issue
3
Digital Object Identifier (DOI)
10.1371/journal.pone.0213143
Recommended Citation
Weltzin, Maegan M.; George, Andrew A.; Lukas, Ronald J.; and Whiteaker, Paul, "Distinctive Single-Channel Properties Of α4β2-Nicotinic Acetylcholine Receptor Isoforms" (2019). Translational Neuroscience. 209.
https://scholar.barrowneuro.org/neurobiology/209