The role of the β9–10 linker in nicotinic acetylcholine receptor selectivity

• Published in: The FASEB journal 2012-04, Vol.26 (S1)
• Main Authors: Nemecz, Akos, Ho, Kwok-yiu, Talley, Todd, Taylor, Palmer
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.26.1_supplement.lb579

Abstract only 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)