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The role of the β9–10 linker in nicotinic acetylcholine receptor selectivity
Author(s) -
Nemecz Akos,
Ho Kwok-yiu,
Talley Todd,
Taylor Palmer
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb579
Subject(s) - homomeric , acetylcholine receptor , nicotinic acetylcholine receptor , ligand gated ion channel , linker , chemistry , nicotinic agonist , ligand (biochemistry) , cys loop receptors , ion channel , protein subunit , receptor , biochemistry , stereochemistry , biophysics , biology , gene , computer science , operating system
The cys‐loop family of ligand‐gated ion channels plays an important role in the chemical‐to‐electrical transduction of neuronal signaling. The nicotinic acetylcholine receptors (nAChRs) may be linked to nicotine addiction, and show possible genetic linkages to such diseases as Alzheimer's and schizophrenia. The discovery of a homologous homomeric soluble snail acetylcholine binding protein provided a structural surrogate of the extracellular ligand‐binding domain. Systematic mutations of the soluble Aplysia californica achieved sequences resembling α7‐nAChR at the subunit interfaces. Here we look specifically at the beta 9–10 linker (C‐loop) and mutate the sequence to every human alpha sequence. These alpha C‐loop mutants were characterized structurally, via x‐ray crystallography, and functionally using a series of ligands selective for each alpha receptor subtype. In some situations ligands showed similar selectivity as the full‐length receptor subtypes, whereas in most situations the flexible C‐loop was not clearly not responsible for the selective property of the ligands tested. (Supported by: U01‐DA 019372, GM07752‐29)