Intramembrane Aromatic Interactions Influence the Lipid Sensitivities of Pentameric Ligand-gated Ion Channels

Carswell, Casey L.; Sun, J.; Baenziger, John E.

doi:10.1074/jbc.m114.624395

Cited by 46 publications

(51 citation statements)

References 60 publications

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“…ELIC, with no aromatic interactions in the C-terminal half of M4 exhibits weak M4-M1/M3 interactions in this region. ELIC is more sensitive than GLIC to M4 targeting modulators, such as the CMS mutation and lipids, although aromatic substitutions at the M4-M1/M3 abrogates sensitivity to both (Carswell et al, 2015). The nAChR with relatively few inter-α-helix aromatic interactions, likely exhibits relatively weak M4-M1/M3 interactions along the entire length of M4, and is even more sensitive than ELIC to both the CMS mutation and lipids.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In the same PC membranes, ELIC does not gate open in response to agonist binding. An ELIC mutant with engineering aromatic interactions at the M4eM1/M3 interface to tighten M4 binding, however, retains channel activity in these minimal PC membranes (Carswell et al, 2014). Aromatic interactions at this interface, which strengthen the apparent binding of M4 to M1/M3, thus appear to play a role in the sensitivity of these prokaryotic pLGICs to their surrounding membrane.…”

Section: Interhelical Chemistry and The Sensitivity Of Plgics To Potementioning

confidence: 97%

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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“…This lack of function may be due to the absence of effective post-M4 aromatic interactions. Significantly, engineering the post-M4 aromatic cluster into ELIC restores the ability of ELIC to gate open in PC bilayers [128]. Modulatable post-M4-M1/M3 interactions thus play a role in ELIC lipid-sensing.…”

Section: Testing the Role Of M4 In Plgic Lipid-sensingmentioning

confidence: 98%

“…Protocols for reconstituting GLIC and ELIC into lipid bilayers have been developed [124][125][126][127][128]. As noted, the extensive aromatic network at the M4-M1/M3 interface in GLIC contributes to relatively strong M4-M1/M3 interactions along the entire length of M4.…”

Section: Testing the Role Of M4 In Plgic Lipid-sensingmentioning

confidence: 98%

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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Intramembrane Aromatic Interactions Influence the Lipid Sensitivities of Pentameric Ligand-gated Ion Channels

Cited by 46 publications

References 60 publications

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

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

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

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

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