title: The role of the M4 lipid-sensor in the folding, trafficking, and allosteric modulation of nicotinic acetylcholine receptors.
abstract: With the availability of high resolution structural data, increasing attention has focused on the mechanisms by which drugs and endogenous compounds allosterically modulate nicotinic acetylcholine receptor (nAChR) function. Lipids are potent modulators of the nAChR from Torpedo. Membrane lipids influence nAChR function by both conformational selection and kinetic mechanisms, stabilizing varying proportions of pre-existing resting, open, desensitized, and uncoupled conformations, as well as influencing the transitions between these conformational states. Structural and functional data highlight a role for the lipid-exposed M4 transmembrane α-helix of each subunit in lipid sensing, and suggest that lipids influence gating by altering the binding of M4 to the adjacent transmembrane α-helices, M1 and M3. M4 has also been implicated in both the folding and trafficking of nAChRs to the cell surface, as well as in the potentiation of nAChR gating by neurosteroids. Here, we discuss the roles of M4 in the folding, trafficking, and allosteric modulation of nAChRs. We also consider the hypothesis that variable chemistry at the M4-M1/M3 transmembrane α-helical interface in different nAChR subunits governs the capacity for potentiation by activating lipids. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.
authors.forename: Camille M
authors.initials: CM
authors.lastname: Hénault
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.
authors.forename: J P Daniel
authors.initials: JP
authors.lastname: Therien
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.
authors.forename: Corrie J B
authors.initials: CJ
authors.lastname: daCosta
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.
authors.forename: Casey L
authors.initials: CL
authors.lastname: Carswell
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Labriola
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Juranka
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada. Electronic address: John.Baenziger@uottawa.ca.
authors.forename: John E
authors.initials: JE
authors.lastname: Baenziger
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001921:Brain / Q000378:metabolism; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011387:Prokaryotic Cells / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D021381:Protein Transport; D043588:Receptor, Muscarinic M4 / Q000737:chemistry* / Q000378:metabolism*; D040681:Structural Homology, Protein; D014101:Torpedo
chemical_list: D008563:Membrane Lipids; D043588:Receptor, Muscarinic M4
keywords: Assembly; Folding; Lipid-sensing; Lipids; M4; Neurosteroids; Nicotinic acetylcholine receptor; Potentiation; Trafficking; Trans-membrane; Uncoupling