Site-specific mutations of nicotinic acetylcholine receptor at the lipid-protein interface dramatically alter ion channel gating

Li, Lian; Lee, Yung-Hui; Pappone, Pamela A.; Palma, Andrew; McNamee, Mark G.

doi:10.1016/s0006-3495(92)81779-4

Cited by 48 publications

(37 citation statements)

References 6 publications

(11 reference statements)

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“…The location of M4 at the periphery of the TMD led to the suggestion that M4 plays a central role in lipid-sensing (Antollini et al, 2005;Xu et al, 2005). To test this hypothesis, numerous mutations of lipid-facing residues on both Torpedo and muscle-type nAChRs have been constructed, and many were found to alter channel function (Bouzat et al, 1998;Lasalde et al, 1996;Lee et al, 1994;Li et al, 1992;Shen et al, 2006;Tamamizu et al, 2000). These studies confirm that even though M4 is distant from both the agonist site and channel gate, its structure influences gating.…”

Section: Role Of M4 As a Lipid Sensormentioning

confidence: 89%

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

et al. 2015

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Section: Role Of M4 As a Lipid Sensormentioning

confidence: 89%

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

et al. 2015

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“…Although there are likely other sites of action (Althoff et al, 2014; Brannigan et al, 2008; Jones and McNamee, 1988), a role for M4 in lipid-sensing is highlighted by the identification of M4-bound lipids in the crystal structure of GLIC (Bocquet et al, 2009), as well as by mutagenesis data showing that changes in nAChR M4-lipid interactions influence channel function (Bouzat et al, 1998; Lasalde et al, 1996; Lee et al, 1994; Li et al, 1992; Shen et al, 2006; Tamamizu et al, 2000). M4 is also the site of action for neurosteroids (Hosie et al, 2006; Paradiso et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Lipid-facing mutations in M4 of the muscle-type nAChR influence channel gating, with at least one leading to a congenital myasthenic syndrome (CMS)(Bouzat et al, 1998; Lasalde et al, 1996; Lee et al, 1994; Li et al, 1992; Shen et al, 2006; Tamamizu et al, 2000). M4 extends beyond the bilayer to interact directly with the β6–β7 loop (often referred to as the Cys-loop), a key structure at the ECD/TMD interface that participates in channel gating.…”

mentioning

confidence: 99%

Role of the Fourth Transmembrane α Helix in the Allosteric Modulation of Pentameric Ligand-Gated Ion Channels

Carswell¹,

Hénault²,

Murlidaran

et al. 2015

Structure

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Summary The gating of pentameric ligand gated ion channels is sensitive to a variety of allosteric modulators that act on structures that are peripheral to those involved in the allosteric pathway leading from the agonist site to the channel gate. One such structure, the lipid-exposed transmembrane α-helix, M4, is the target of lipids, neurosteroids, and disease-causing mutations. Here we show that M4 interactions with the adjacent transmembrane α-helices, M1 and M3, modulate pLGIC function. Enhanced M4 interactions promote, while ineffective interactions reduce channel function. The interface chemistry governs the intrinsic strength of M4-M1/M3 inter-helical interactions, both influencing channel gating and imparting distinct susceptibilities to the potentiating effects of a lipid-facing M4 congenital myasthenic syndrome mutation. Through aromatic substitutions, functional studies, and molecular dynamics simulations, we elucidate a mechanism by which M4 modulates channel function.

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“…Two of the three lipid binding sites observed in the crystal structure of GLIC are found at the interfaces between M4 and the adjacent TMD α-helices M1 and M3 (see Section 4.1). Numerous mutations of M4 lipid-facing residues on both Torpedo and muscle-type nAChRs, which alter M4-lipid interactions, also alter channel function [10,[78][79][80][81][82], with the amino acid changes studied to date typically affecting channel opening and closing rates [81,83,84]. Finally, M4-swapped chimeric constructs of the homologous glycine receptor α1 and α3 subunits demonstrate that subunit-specific agonist efficacy is driven in large part by M4, with agonist sensitivity mediated by differences in M4-lipid interactions [85].…”

Section: Sites Of Lipid-nachr Interactionsmentioning

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.

show abstract

Site-specific mutations of nicotinic acetylcholine receptor at the lipid-protein interface dramatically alter ion channel gating

Cited by 48 publications

References 6 publications

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

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

Role of the Fourth Transmembrane α Helix in the Allosteric Modulation of Pentameric Ligand-Gated Ion Channels

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

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