RIC-3 expression and splicing regulate nAChR functional expression

• Published in: Molecular brain Vol. 9; no. 1; p. 47
• Main Authors: Ben-David, Yael, Mizrachi, Tehila, Kagan, Sarah, Krisher, Tamar, Cohen, Emiliano, Brenner, Talma, Treinin, Millet
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 29-04-2016; BioMed Central
• Subjects: Acetylcholine - pharmacology; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Alternative Splicing - drug effects; Alternative Splicing - genetics; Analysis; Animals; Brain - drug effects; Brain - metabolism; Gene expression; In Situ Hybridization; Inflammation - pathology; Influence; Ion Channel Gating - drug effects; Ion channels; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Nicotinic receptors; Protein Domains; Protein Isoforms - metabolism; Protein Subunits - metabolism; RAW 264.7 Cells; Spleen - metabolism; Xenopus laevis; Alternative splicing; Disordered protein; RIC-3; Acetylcholine; Inflammation; Nicotinic acetylcholine receptors (nAChR); Protein maturation
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/s13041-016-0231-5

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.