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Regulation of Nicotinic Acetylcholine Receptor Assembly
Author(s) -
WANAMAKER CHRISTIAN P.,
CHRISTIANSON JOHN C.,
GREEN WILLIAM N.
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1254.009
Subject(s) - protein subunit , endoplasmic reticulum , acetylcholine receptor , chemistry , g alpha subunit , microbiology and biotechnology , cys loop receptors , trimer , gamma subunit , biochemistry , receptor , biophysics , nicotinic acetylcholine receptor , biology , dimer , organic chemistry , gene
A bstract : The four muscle‐type nicotinic acetylcholine receptor (AChR) subunits, α, β, γ, and δ, assemble into functional α 2 βγδ pentamers in the endoplasmic reticulum (ER) through a series of interdependent folding and oligomerization events. The first stable assembly intermediate is a trimer composed of α, β, and γ subunits. The formation of αβγ trimers initiates a series of subunit folding and processing events that allow addition of δ subunits to form αβγδ tetramers. Subunit folding and processing continue with formation of the ligand‐binding sites on the α subunit of αβγδ tetramers and the second α subunit added to assemble α 2 βγδ pentamers. AChR assembly is inefficient. Only 20–30% of synthesized subunits assemble into mature receptors in the ER, while the remaining unassembled subunits are degraded. However, the efficiency of subunit assembly can be regulated under certain conditions leading to higher AChR expression. Increased intracellular cAMP levels cause a 2‐ to 3‐fold increase in AChR assembly efficiency and a comparable increase in surface expression. Additionally, block of ubiquitin‐proteasome degradation appears to enhance AChR assembly and expression. Thus, the regulation of AChR assembly through posttranslational mechanisms is a potential therapeutic target for increasing AChR expression in diseases in which expression is compromised.