title: Lynx1 shifts α4β2 nicotinic receptor subunit stoichiometry by affecting assembly in the endoplasmic reticulum.
abstract: Glycosylphosphatidylinositol-anchored neurotoxin-like receptor binding proteins, such as lynx modulators, are topologically positioned to exert pharmacological effects by binding to the extracellular portion of nAChRs. These actions are generally thought to proceed when both lynx and the nAChRs are on the plasma membrane. Here, we demonstrate that lynx1 also exerts effects on α4β2 nAChRs within the endoplasmic reticulum. Lynx1 affects assembly of nascent α4 and β2 subunits and alters the stoichiometry of the receptor population that reaches the plasma membrane. Additionally, these data suggest that lynx1 shifts nAChR stoichiometry to low sensitivity (α4)3(β2)2 pentamers primarily through this interaction in the endoplasmic reticulum, rather than solely via direct modulation of activity on the plasma membrane. To our knowledge, these data represent the first test of the hypothesis that a lynx family member, or indeed any glycosylphosphatidylinositol-anchored protein, could act within the cell to alter assembly of a multisubunit protein.
authors.affiliation: From the Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125.
authors.forename: Weston A
authors.initials: WA
authors.lastname: Nichols
authors.affiliation: From the Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Henderson
authors.affiliation: From the Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125.
authors.forename: Caroline
authors.initials: C
authors.lastname: Yu
authors.affiliation: From the Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125.
authors.forename: Rell L
authors.initials: RL
authors.lastname: Parker
authors.affiliation: the Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506, and.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Richards
authors.affiliation: From the Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125.
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.affiliation: From the Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, the Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015 jmm312@lehigh.edu.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Miwa
mesh_terms: D000109:Acetylcholine / Q000737:chemistry; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D049452:Green Fluorescent Proteins / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal; D009479:Neuropeptides / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011978:Receptors, Nicotinic / Q000737:chemistry*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C120222:Lynx1 protein, mouse; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D049452:Green Fluorescent Proteins; D003545:Cysteine; D000109:Acetylcholine
keywords: Cys Loop Receptor; Glycosylphosphatidylinositol (GPI Anchor); Nicotinic Acetylcholine Receptors (nAChR); Snake Venom; Toxin