Department
neurobiology
Document Type
Article
Abstract
Despite the apparent function of naturally expressed mammalian α6*-nicotinic acetylcholine receptors (α6*-nAChR; where*indicates the known or possible presence of additional subunits), their functional and heterologous expression has been difficult. Here, we report that coexpression with wild-type β3 subunits abolishes the small amount of function typically seen for all-human or all-mouse α6β4*-nAChR expressed in Xenopus oocytes. However, levels of function and agonist potencies are markedly increased, and there is atropine-sensitive blockade of spontaneous channel opening upon coexpression of α6 and β4 subunits with mutant β3 subunits harboring valine-to-serine mutations at 9′- or 13′-positions. There is no function when α6 and β2 subunits are expressed alone or in the presence of wild-type or mutant β3 subunits. Interestingly, hybrid nAChR containing mouse α6 and human (h) β4 subunits have function potentiated rather than suppressed by coexpression with wild-type hβ3 subunits and potentiated further upon coexpression with hβ3 V9,S subunits. Studies using nAChR chimeric mouse/human α6 subunits indicated that residues involved in effects seen with hybrid nAChR are located in the α6 subunit N-terminal domain. More specifically, nAChR hα6 subunit residues Asn-143 and Met-145 are important for dominant-negative effects of nAChR hβ3 subunits on hα6hβ4-nAChR function. Asn-143 and additional residues in the N-terminal domain of nAChR hα6 subunits are involved in the gain-of-function effects of nAChR hβ3 V9,S subunits on α6β2*-nAChR function. These studies illuminate the structural bases for effects of β3 subunits on α6*-nAChR function and suggest that unique subunit interfaces involving the complementary rather than the primary face of α6 subunits are involved. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication Date
11-4-2011
Publication Title
Journal of Biological Chemistry
ISSN
00219258
Volume
286
Issue
44
First Page
37976
Last Page
37989
Digital Object Identifier (DOI)
10.1074/jbc.M111.263673
Recommended Citation
Dash, Bhagirathi; Bhakta, Minoti; Chang, Yongchang; and Lukas, Ronald J., "Identification Of N-Terminal Extracellular Domain Determinants In Nicotinic Acetylcholine Receptor (Nachr) α6 Subunits That Influence Effects Of Wild-Type Or Mutant β3 Subunits On Function Of α6β2*- Or α6β4*-Nachr" (2011). Translational Neuroscience. 231.
https://scholar.barrowneuro.org/neurobiology/231