title: RIC-3 expression and splicing regulate nAChR functional expression.
abstract: The nicotinic acetylcholine receptors form a large and diverse family of acetylcholine gated ion channels having diverse roles in the central nervous system. Maturation of nicotinic acetylcholine receptors is a complex and inefficient process requiring assistance from multiple cellular factors including RIC-3, a functionally conserved endoplasmic reticulum-resident protein and nicotinic acetylcholine receptor-specific chaperone. In mammals and in Drosophila melanogaster RIC-3 is alternatively spliced to produce multiple isoforms.
  
  
  
  We used electrophysiological analysis in Xenopus laevis oocytes, in situ hybridization, and quantitative real-time polymerase chain reaction assays to investigate regulation of RIC-3's expression and splicing and its effects on the expression of three major neuronal nicotinic acetylcholine receptors. We found that RIC-3 expression level and splicing affect nicotinic acetylcholine receptor functional expression and that two conserved RIC-3 isoforms express in the brain differentially. Moreover, in immune cells RIC-3 expression and splicing are regulated by inflammatory signals.
  
  
  
  Regulation of expression level and splicing of RIC-3 in brain and in immune cells following inflammation enables regulation of nicotinic acetylcholine receptor functional expression. Specifically, in immune cells such regulation via effects on α7 nicotinic acetylcholine receptor, known to function in the cholinergic anti-inflammatory pathway, may have a role in neuroinflammatory diseases.
authors.affiliation: Department of Medical Neurobiology, Faculty of Medicine, The Hebrew University, Ein Kerem, P.O. Box 12271, Jerusalem, 91120, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Ben-David
authors.affiliation: Department of Neurology, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Tehila
authors.initials: T
authors.lastname: Mizrachi
authors.affiliation: Department of Medical Neurobiology, Faculty of Medicine, The Hebrew University, Ein Kerem, P.O. Box 12271, Jerusalem, 91120, Israel.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kagan
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Krisher
authors.affiliation: Department of Medical Neurobiology, Faculty of Medicine, The Hebrew University, Ein Kerem, P.O. Box 12271, Jerusalem, 91120, Israel.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Cohen
authors.affiliation: Department of Neurology, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Talma
authors.initials: T
authors.lastname: Brenner
authors.affiliation: Department of Medical Neurobiology, Faculty of Medicine, The Hebrew University, Ein Kerem, P.O. Box 12271, Jerusalem, 91120, Israel. millet.treinin@mail.huji.ac.il.
authors.forename: Millet
authors.initials: M
authors.lastname: Treinin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D017403:In Situ Hybridization; D007249:Inflammation / Q000473:pathology; D015640:Ion Channel Gating / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D000072417:Protein Domains; D020033:Protein Isoforms / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D000067996:RAW 264.7 Cells; D013154:Spleen / Q000378:metabolism; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; D021122:Protein Subunits; C544672:Ric-3 protein, mouse; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000109:Acetylcholine
keywords: Acetylcholine; Alternative splicing; Disordered protein; Inflammation; Nicotinic acetylcholine receptors (nAChR); Protein maturation; RIC-3