The role of the M4 lipid-sensor in the folding, trafficking, and allosteric modulation of nicotinic acetylcholine receptors

Hénault, Camille M.; Sun, J.; Therien, J. P. Daniel; daCosta, Corrie J.B.; Carswell, Casey L.; Labriola, Jonathan M.; Juranka, Peter F.; Baenziger, John E.

doi:10.1016/j.neuropharm.2014.11.011

Cited by 39 publications

(19 citation statements)

References 126 publications

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“…Recent data have indicated that the M4 helix is a highly important region of pLGICs that is involved in allosteric modulation of receptor function via interaction with lipids, the adjacent M1 and M3 helices, and the extracellular domain ( 29 , 30 ). The final sensitive residue identified in GLIC, Pro-299, is located in the middle of the M4 helix ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Perturbation of Critical Prolines in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC) Supports Conserved Gating Motions among Cys-loop Receptors

Rienzo

Rocchi

Threatt

et al. 2016

Journal of Biological Chemistry

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Gloeobacter violaceus ligand-gated ion channel (GLIC) has served as a valuable structural and functional model for the eukaryotic Cys-loop receptor superfamily. In Cys-loop and other receptors, we have previously demonstrated the crucial roles played by several conserved prolines. Here we explore the role of prolines in the gating transitions of GLIC. As conventional substitutions at some positions resulted in nonfunctional proteins, we used in vivo non-canonical amino acid mutagenesis to determine the specific structural requirements at these sites. Receptors were expressed heterologously in Xenopus laevis oocytes, and whole-cell electrophysiology was used to monitor channel activity. Pro-119 in the Cys-loop, Pro-198 and Pro-203 in the M1 helix, and Pro-299 in the M4 helix were sensitive to substitution, and distinct roles in receptor activity were revealed for each. In the context of the available structural data for GLIC, the behaviors of Pro-119, Pro-203, and Pro-299 mutants are consistent with earlier proline mutagenesis work. However, the Pro-198 site displays a unique phenotype that gives evidence of the importance of the region surrounding this residue for the correct functioning of GLIC.

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Section: Resultsmentioning

confidence: 99%

Perturbation of Critical Prolines in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC) Supports Conserved Gating Motions among Cys-loop Receptors

Rienzo

Rocchi

Threatt

et al. 2016

Journal of Biological Chemistry

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“…Although many factors are known to influence mammalian nAChR trafficking [129][130][131] (see also [132]), a role for M4 binding to M1/M3 has been clearly demonstrated in the homologous glycine receptor. When expressed in oocytes, the glycine receptor is cleaved within the intracellular loop, but still undergoes agonist-induced channel gating.…”

Section: Lipids and The Folding And Trafficking Of Nachrsmentioning

confidence: 99%

Nicotinic acetylcholine receptor–lipid interactions: Mechanistic insight and biological function

Baenziger

Hénault

Therien

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Membrane lipids are potent modulators of the nicotinic acetylcholine receptor (nAChR) from Torpedo. Lipids influence nAChR function by both conformational selection and kinetic mechanisms, stabilizing varying proportions of activatable versus non-activatable conformations, as well as influencing the transitions between these conformational states. Of note, some membranes stabilize an electrically silent uncoupled conformation that binds agonist but does not undergo agonist-induced conformational transitions. The uncoupled nAChR, however, does transition to activatable conformations in relatively thick lipid bilayers, such as those found in lipid rafts. In this review, we discuss current understanding of lipid-nAChR interactions in the context of increasingly available high resolution structural and functional data. These data highlight different sites of lipid action, including the lipid-exposed M4 transmembrane α-helix. Current evidence suggests that lipids alter nAChR function by modulating interactions between M4 and the adjacent transmembrane α-helices, M1 and M3. These interactions have also been implicated in both the folding and trafficking of nAChRs to the cell surface. We review current mechanistic understanding of lipid-nAChR interactions, and highlight potential biological roles for lipid-nAChR interactions in modulating the synaptic response. This article is part of a Special Issue entitled: Lipid-protein interactions.

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“…Considerable work has focused on the M4 α-helix in each subunit of the nAChR as the transducer of lipid-protein interactions 11 . M4 is the outermost α-helix in the TMD of each subunit and thus forms the primary contact with lipids (Fig.…”

Section: Introductionmentioning

confidence: 99%

An allosteric link connecting the lipid-protein interface to the gating of the nicotinic acetylcholine receptor

Domville

Baenziger

2018

Sci Rep

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The mechanisms underlying lipid-sensing by membrane proteins is of considerable biological importance. A unifying mechanistic question is how a change in structure at the lipid-protein interface is translated through the transmembrane domain to influence structures critical to protein function. Gating of the nicotinic acetylcholine receptor (nAChR) is sensitive to its lipid environment. To understand how changes at the lipid-protein interface influence gating, we examined how a mutation at position 418 on the lipid-facing surface of the outer most M4 transmembrane α-helix alters the energetic couplings between M4 and the remainder of the transmembrane domain. Human muscle nAChR is sensitive to mutations at position 418, with the Cys-to-Trp mutation resulting in a 16-fold potentiation in function that leads to a congenital myasthenic syndrome. Energetic coupling between M4 and the Cys-loop, a key structure implicated in gating, do not change with C418W. Instead, Trp418 and an adjacent residue couple energetically with residues on the M1 transmembrane α-helix, leading to a reorientation of M1 that stabilizes the open state. We thus identify an allosteric link connecting the lipid-protein interface of the nAChR to altered channel function.

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The role of the M4 lipid-sensor in the folding, trafficking, and allosteric modulation of nicotinic acetylcholine receptors

Cited by 39 publications

References 126 publications

Perturbation of Critical Prolines in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC) Supports Conserved Gating Motions among Cys-loop Receptors

Perturbation of Critical Prolines in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC) Supports Conserved Gating Motions among Cys-loop Receptors

Nicotinic acetylcholine receptor–lipid interactions: Mechanistic insight and biological function

An allosteric link connecting the lipid-protein interface to the gating of the nicotinic acetylcholine receptor

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