4.7 Review

Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

Related references

Note: Only part of the references are listed.
Article Multidisciplinary Sciences

Mechanisms of inhibition and activation of extrasynaptic alpha beta GABA(A) receptors

Vikram Babu Kasaragod et al.

Summary: Type A GABA receptors are a diverse population in the mammalian brain, and mutations in these receptors are linked to epilepsy and insomnia. Altered function of extrasynaptic receptors is implicated in insomnia, stroke, and certain syndromes. This study investigates the structures of the predominantly extrasynaptic alpha beta GABA(A) receptor class and explains their distinct features related to tonic signaling.

NATURE (2022)

Article Neurosciences

Conformational transitions and ligand-binding to a muscle-type nicotinic acetylcholine receptor

Eleftherios Zarkadas et al.

Summary: This study used cryo-EM to determine the structure of the muscle-type nicotinic acetylcholine receptor from the electric fish Torpedo. The results shed light on the structural changes and functional states of the receptor, uncovering the important role of subunits in channel gating and explaining the lower potency of nicotine at muscle nicotinic receptors compared to neuronal ones.

NEURON (2022)

Article Biology

Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites

Noah M. Dietzen et al.

Summary: Polyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs), but the specific mechanism of inhibition is unclear. This study found that docosahexaenoic acid (DHA), a type of PUFA, is more effective at inhibiting the ELIC receptor's response to agonists compared to other fatty acids. Using experiments and simulations, the researchers identified two binding sites for fatty acids in the outer transmembrane domain (TMD) of ELIC, and demonstrated that DHA selectively binds to these sites and inhibits ELIC by binding to a specific intrasubunit site.

ELIFE (2022)

Review Physiology

Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

Wayland W. L. Cheng et al.

Summary: Lipids modulate the function of ion channels through direct lipid-protein interactions. Cryo-EM studies have identified lipid binding sites on ion channels, but the role of these sites in lipid modulation is not fully understood. These binding sites also coincide with sites for other allosteric modulators or drugs, suggesting that lipids act as endogenous allosteric modulators. This review focuses on lipid-drug binding sites in pentameric ligand-gated ion channels and transient receptor potential channels, highlighting the shared sites for phospholipids, sterols, anesthetics, and vanilloids. The implications of lipid binding at these sites, such as potential changes in drug potency and guiding drug design through protein-lipid interactions, are discussed. However, further studies are needed to fully understand the mechanisms of lipid modulation at these sites.

FRONTIERS IN PHYSIOLOGY (2022)

Article Multidisciplinary Sciences

Differential assembly diversifies GABA(A) receptor structures and signalling

Andrija Sente et al.

Summary: In this study, the structures and arrangement diversity of GABA(A)Rs receptors were determined using cryogenic electron microscopy. It was found that different arrangements can affect receptor responses to modulators and that GABA(A)Rs receptors can simultaneously respond to two neurotransmitters. Through calculations and simulations, the researchers propose that differential assembly is a mechanism for regulating the function of GABA(A)Rs.

NATURE (2022)

Article Biochemistry & Molecular Biology

Structural mechanism of muscle nicotinic receptor desensitization and block by curare

Md Mahfuzur Rahman et al.

Summary: This study reveals the structural basis of how the nicotinic acetylcholine receptor desensitizes in response to agonists and how the poison arrow toxin curare antagonizes the channel.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2022)

Article Microscopy

Protein-lipid interplay at the neuromuscular junction

Nigel Unwin

Summary: Many new structures of membrane proteins have been determined in the last decade, but the interaction between proteins and lipids has not received much attention. Cryo-EM images show that cholesterol segregates preferentially around the ion channel, the nicotinic acetylcholine receptor, and interacts with specific sites in both leaflets of the bilayer. Cholesterol not only maintains the transmembrane alpha-helical architecture, but also forms microdomains that link one channel to the next. This article discusses the organization of protein-lipid in the cholinergic postsynaptic membrane and its physiological implications. It suggests that cooperative interactions facilitated by the protein-lipid arrangement help spread channel activation and enhance the postsynaptic response.

MICROSCOPY (2022)

Article Biochemistry & Molecular Biology

M4, the Outermost Helix, is Extensively Involved in Opening of the α4ß2 nACh Receptor

Susanne M. Mesoy et al.

Summary: This study investigated the role of M4 residues in the alpha 4 ss 2 nAChR using site-directed mutagenesis. Results showed that two mutant receptors had altered EC(50)s, 13 were nonfunctional, and coexpression with chaperones allowed 4 to respond to agonist. The remaining 9 mutants showed potential involvement in channel opening based on radioligand binding studies.

ACS CHEMICAL NEUROSCIENCE (2021)

Article Biochemistry & Molecular Biology

Mechanism of gating and partial agonist action in the glycine receptor

Jie Yu et al.

Summary: Using electrophysiology and cryo-EM reconstructions, this study investigated the mechanism of partial agonist action on neurotransmitter receptors, revealing new conformational states along the receptor reaction pathway. The results demonstrated that partial agonists can occupy closed channel states bound by agonists, affecting the receptor channel's open probability.
Article Multidisciplinary Sciences

Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers

Yingyi Zhang et al.

Summary: The study presents structures of the pLGIC 5-HT3A serotonin receptor reconstituted into lipid bilayer discs, showing lipid-protein interactions and asymmetric activation of the homopentameric receptor.

NATURE COMMUNICATIONS (2021)

Article Biochemical Research Methods

State-dependent protein-lipid interactions of a pentameric ligand-gated ion channel in a neuronal membrane

Marc A. Damgen et al.

Summary: The study on pentameric ligand-gated ion channels (pLGICs) using molecular dynamics simulations revealed key lipid-protein interactions dependent on the channel state, potentially aiding in the design of lipid-like allosteric drugs in the future.

PLOS COMPUTATIONAL BIOLOGY (2021)

Article Biochemistry & Molecular Biology

Structure and gating mechanism of the α7 nicotinic acetylcholine receptor

Colleen M. Noviello et al.

Summary: The alpha 7 nicotinic acetylcholine receptor plays critical roles in the central nervous system and the cholinergic inflammatory pathway as a ligand-gated ion channel. Recent cryo-EM structures of the human alpha 7 nicotinic receptor in different states have provided insights into its gating cycle and functional elements, including a C-terminal latch and an anionic ring that contribute to its high conductance and calcium permeability. Comparisons among the alpha 7 structures have revealed divergence in gating mechanisms within the Cys-loop receptor superfamily.
Article Biology

Unmasking coupling between channel gating and ion permeation in the muscle nicotinic receptor

John R. Strikwerda et al.

Summary: This research on muscle nicotinic receptors reveals a coupling between channel gating and ion permeation through structural perturbation, showing that a charge-neutralizing mutation can suppress channel gating and impact unitary current amplitude. The study also demonstrates that the power spectrum and current relaxations are described by a theory where structural motions contribute to both channel gating and ion conduction. Coupling is manifested as a transient increase in open channel current upon channel opening and a decrease upon channel closing.

ELIFE (2021)

Article Biochemistry & Molecular Biology

A Single Mutation in the Outer Lipid-Facing Helix of a Pentameric Ligand-Gated Ion Channel Affects Channel Function Through a Radially-Propagating Mechanism

Alessandro Crnjar et al.

Summary: Pentameric ligand-gated ion channels (pLGICs) play a crucial role in fast synaptic transmission and are important drug targets. The M4 helix is key to channel opening, connecting radially through M1 to the hydrophobic gate on the pore-lining helix M2.

FRONTIERS IN MOLECULAR BIOSCIENCES (2021)

Article Pharmacology & Pharmacy

Probing the molecular basis for signal transduction through the Zinc-Activated Channel (ZAC)

Nawid Madjroh et al.

Summary: The molecular mechanisms underlying ZAC signaling were explored using Xenopus oocytes, revealing that Zn2+ and protons predominantly activate ZAC through its extracellular domain. Despite differences in identified agonists and channel characteristics, the signal transduction of ZAC appears to undergo similar conformational transitions as classical CLRs.

BIOCHEMICAL PHARMACOLOGY (2021)

Article Biochemistry & Molecular Biology

Regulation of a pentameric ligand-gated ion channel by a semiconserved cationic lipid-binding site

Akshay Sridhar et al.

Summary: This study reveals a potential lipid-binding site at a residue in the ELIC channel's transmembrane domain, with simulations showing preferential binding of positively charged lipids, particularly interacting with residue W206, through cation-pi binding. Polar contacts from other regions of the protein and mutagenesis experiments further support lipid binding. Mutations at this site in GABA(A) receptors can alter the affinity of the agonist response, suggesting a potential role in channel gating.

JOURNAL OF BIOLOGICAL CHEMISTRY (2021)

Article Multidisciplinary Sciences

Architecture and assembly mechanism of native glycine receptors

Hongtao Zhu et al.

Summary: The study presents the cryo-electron microscopy structures of native GlyRs, revealing a predominant subunit stoichiometry of 4 alpha:1 beta and unique structural features at the beta(+)-alpha(-) interface. The presence of a phenylalanine residue in the beta-subunit disrupts the canonical picrotoxin site, impacting receptor symmetry and ion channel pharmacology. Furthermore, incomplete receptor complexes and partially assembled alpha-trimers and alpha-tetramers are identified through structural elucidation.

NATURE (2021)

Article Neurosciences

Characterization of the subunit composition and structure of adult human glycine receptors

Hailong Yu et al.

Summary: The strychnine-sensitive pentameric glycine receptor plays a crucial role in fast inhibitory neurotransmission in the mammalian nervous system. The study found that a single beta subunit in each GlyR is responsible for the characteristic electrophysiological properties of heteromeric GlyR.

NEURON (2021)

Article Multidisciplinary Sciences

Structure and function at the lipid-protein interface of a pentameric ligand-gated ion channel

Pramod Kumar et al.

Summary: The study focused on characterizing natively bound lipids in the superfamily of pentameric ligand-gated ion channels (pLGICs) using cryogenic electron microscopy. It identified two types of tightly bound lipids at the protein-bulk-membrane interface, shedding light on the interaction between membrane proteins and lipids.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2021)

Article Biophysics

Interfacial binding sites for cholesterol on GABAA receptors and competition with neurosteroids

Anthony G. Lee

Summary: GABA(A) receptors in the brain are located in the outer membranes of brain cells with high cholesterol concentration. Through molecular docking, cholesterol binding sites on the transmembrane surfaces of the receptors were identified. The receptors are pentameric, with TM surfaces consisting of five facets each with potential binding sites for cholesterol.

BIOPHYSICAL JOURNAL (2021)

Article Multidisciplinary Sciences

Microsecond-timescale simulations suggest 5-HT-mediated preactivation of the 5-HT3A serotonin receptor

Nicholas B. Guros et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2020)

Article Biochemistry & Molecular Biology

The M4 Helix Is Involved in α7 nACh Receptor Function

Ana R. G. M. da Costa Couto et al.

ACS CHEMICAL NEUROSCIENCE (2020)

Review Pharmacology & Pharmacy

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

Cesar O. Lara et al.

FRONTIERS IN PHARMACOLOGY (2020)

Article Multidisciplinary Sciences

Structural basis for allosteric transitions of a multidomain pentameric ligand-gated ion channel

Haidai Hu et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2020)

Article Biochemistry & Molecular Biology

Membrane cholesterol dependence of cannabinoid modulation of glycine receptor

Lei Yao et al.

FASEB JOURNAL (2020)

Article Chemistry, Multidisciplinary

Protein-lioid architecture of a cholinergic postsynaptic membrane

Nigel Unwin

IUCRJ (2020)

Review Biochemistry & Molecular Biology

Structural basis for the modulation of pentameric ligand-gated ion channel function by lipids

Mackenzie J. Thompson et al.

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES (2020)

Article Biochemistry & Molecular Biology

On the Functional Annotation of Open-Channel Structures in the Glycine Receptor

Adrien Henri Cerdan et al.

STRUCTURE (2020)

Article Biochemistry & Molecular Biology

The Binding of Palonosetron and Other Antiemetic Drugs to the Serotonin 5-HT3 Receptor

Eleftherios Zarkadas et al.

STRUCTURE (2020)

Review Neurosciences

Do Nicotinic Receptors Modulate High-Order Cognitive Processing?

Fani Koukouli et al.

TRENDS IN NEUROSCIENCES (2020)

Article Multidisciplinary Sciences

Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs

Arvind Kumar et al.

NATURE COMMUNICATIONS (2020)

Article Multidisciplinary Sciences

Shared structural mechanisms of general anaesthetics and benzodiazepines

Jeong Joo Kim et al.

NATURE (2020)

Article Chemistry, Medicinal

Drug Development in Channelopathies: Allosteric Modulation of Ligand-Gated and Voltage-Gated Ion Channels

Yanyun Zhang et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

Review Biochemistry & Molecular Biology

Ion channels as lipid sensors: from structures to mechanisms

Mackenzie J. Thompson et al.

NATURE CHEMICAL BIOLOGY (2020)

Review Neurosciences

The Neuromuscular Junction in Health and Disease: Molecular Mechanisms Governing Synaptic Formation and Homeostasis

Pedro M. Rodriguez Cruz et al.

FRONTIERS IN MOLECULAR NEUROSCIENCE (2020)

Article Biochemistry & Molecular Biology

Common binding sites for cholesterol and neurosteroids on a pentameric ligand-gated ion channel

Melissa M. Budelier et al.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS (2019)

Article Multidisciplinary Sciences

Molecular mechanism of setron-mediated inhibition of full-length 5-HT3A receptor

Sandip Basak et al.

NATURE COMMUNICATIONS (2019)

Article Biochemistry & Molecular Biology

A lipid site shapes the agonist response of a pentameric ligand-gated ion channel

Camille M. Henault et al.

NATURE CHEMICAL BIOLOGY (2019)

Article Multidisciplinary Sciences

Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer

Duncan Laverty et al.

NATURE (2019)

Article Multidisciplinary Sciences

GABAA receptor signalling mechanisms revealed by structural pharmacology

Simonas Masiulis et al.

NATURE (2019)

Article Biochemistry & Molecular Biology

Characterization of Residues in the 5-HT3 Receptor M4 Region That Contribute to Function

Susanne Mesoy et al.

ACS CHEMICAL NEUROSCIENCE (2019)

Review Neurosciences

The dual-gate model for pentameric ligand-gated ion channels activation and desensitization

Marc Gielen et al.

JOURNAL OF PHYSIOLOGY-LONDON (2018)

Article Biochemistry & Molecular Biology

Saposin Lipid Nanoparticles: A Highly Versatile and Modular Tool for Membrane Protein Research

Ali Flayhan et al.

STRUCTURE (2018)

Article Multidisciplinary Sciences

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

Jaimee A. Domville et al.

SCIENTIFIC REPORTS (2018)

Article Neurosciences

The roles of aromatic residues in the glycine receptor transmembrane domain

Bijun Tang et al.

BMC NEUROSCIENCE (2018)

Article Multidisciplinary Sciences

Structure of a human synaptic GABAA receptor

Shaotong Zhu et al.

NATURE (2018)

Article Multidisciplinary Sciences

Structural principles of distinct assemblies of the human α4β2 nicotinic receptor

Richard M. Walsh et al.

NATURE (2018)

Article Multidisciplinary Sciences

Structural basis of neurosteroid anesthetic action on GABAA receptors

Qiang Chen et al.

NATURE COMMUNICATIONS (2018)

Article Multidisciplinary Sciences

Conformational transitions of the serotonin 5-HT3 receptor

Lucie Polovinkin et al.

NATURE (2018)

Article Biochemistry & Molecular Biology

Aromatic Residues in the Fourth Transmembrane-Spanning Helix M4 Are Important for GABAρ Receptor Function

James Cory-Wright et al.

ACS CHEMICAL NEUROSCIENCE (2018)

Article Physiology

A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip

Shaweta Gupta et al.

JOURNAL OF GENERAL PHYSIOLOGY (2017)

Article Biochemistry & Molecular Biology

Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites

Duncan Laverty et al.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2017)

Article Biochemistry & Molecular Biology

Structural basis for GABAA receptor potentiation by neurosteroids

Paul S. Miller et al.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2017)

Article Biochemistry & Molecular Biology

Crystal Structures of Human GlyRα3 Bound to Ivermectin

Xin Huang et al.

STRUCTURE (2017)

Article Biochemistry & Molecular Biology

Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites

Duncan Laverty et al.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2017)

Article Biochemistry & Molecular Biology

Structural basis for GABAA receptor potentiation by neurosteroids

Paul S. Miller et al.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2017)

Article Chemistry, Medicinal

Progress in the discovery of small molecule modulators of the Cys-loop superfamily receptors

Brian A. Sparling et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2017)

Article Biochemistry & Molecular Biology

Heterogeneous Inhibition in Macroscopic Current Responses of Four Nicotinic Acetylcholine Receptor Subtypes by Cholesterol Enrichment

Carlos A. Baez-Pagan et al.

JOURNAL OF MEMBRANE BIOLOGY (2016)

Article Multidisciplinary Sciences

Site Directed Spin Labeling and EPR Spectroscopic Studies of Pentameric Ligand-Gated Ion Channels

Sandip Basak et al.

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS (2016)

Article Biochemistry & Molecular Biology

Phylogenetic conservation of protein-lipid motifs in pentameric ligand-gated ion channels

Francisco J. Barrantes

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES (2015)

Review Biochemistry & Molecular Biology

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

John E. Baenziger et al.

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES (2015)

Article Multidisciplinary Sciences

Glycine receptor mechanism elucidated by electron cryo-microscopy

Juan Du et al.

NATURE (2015)

Article Biochemistry & Molecular Biology

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

Casey L. Carswell et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2015)

Article Biochemistry & Molecular Biology

Structural Basis for Allosteric Coupling at the Membrane-Protein Interface in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC)

Phanindra Velisetty et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2014)

Article Multidisciplinary Sciences

X-ray structure of the mouse serotonin 5-HT3 receptor

Gherici Hassaine et al.

NATURE (2014)

Article Biochemistry & Molecular Biology

Structural Sensitivity of a Prokaryotic Pentameric Ligand-gated Ion Channel to Its Membrane Environment

Jonathan M. Labriola et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2013)

Article Biochemistry & Molecular Biology

A distinct mechanism for activating uncoupled nicotinic acetylcholine receptors

Corrie J. B. daCosta et al.

NATURE CHEMICAL BIOLOGY (2013)

Article Biochemistry & Molecular Biology

Desensitization Mechanism in Prokaryotic Ligand-gated Ion Channel

Phanindra Velisetty et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2012)

Article Biochemistry & Molecular Biology

Gating Movement of Acetylcholine Receptor Caught by Plunge-Freezing

Nigel Unwin et al.

JOURNAL OF MOLECULAR BIOLOGY (2012)

Article Multidisciplinary Sciences

Principles of activation and permeation in an anion-selective Cys-loop receptor

Ryan E. Hibbs et al.

NATURE (2011)

Article Biochemistry & Molecular Biology

An intramembrane aromatic network determines pentameric assembly of Cys-loop receptors

Svenja Haeger et al.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2010)

Article Biochemistry & Molecular Biology

A Lipid-dependent Uncoupled Conformation of the Acetylcholine Receptor

Corrie J. B. daCosta et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2009)

Article Biochemistry & Molecular Biology

Anionic Lipids Allosterically Modulate Multiple Nicotinic Acetylcholine Receptor Conformational Equilibria

Corrie J. B. daCosta et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2009)

Article Biochemistry & Molecular Biology

The M4 transmembrane segment contributes to agonist efficacy differences between 1 and 3 glycine receptors

Xuebin Chen et al.

MOLECULAR MEMBRANE BIOLOGY (2009)

Article Neurosciences

Importance of the C-terminus of the human 5-HT3A receptor subunit

Amy S. Butler et al.

NEUROPHARMACOLOGY (2009)

Article Multidisciplinary Sciences

Embedded cholesterol in the nicotinic acetylcholine receptor

Grace Brannigan et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2008)

Article Multidisciplinary Sciences

Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites

Alastair M. Hosie et al.

NATURE (2006)

Article Biochemistry & Molecular Biology

The polarity of lipid-exposed residues contributes to the functional differences between Torpedo and muscle-type nicotinic receptors

Gisila R. Guzman et al.

JOURNAL OF MEMBRANE BIOLOGY (2006)

Article Biochemistry & Molecular Biology

Assessing the lipid requirements of the Torpedo californica nicotinic acetylcholine receptor

AK Hamouda et al.

BIOCHEMISTRY (2006)

Article Chemistry, Multidisciplinary

Not ions alone: Barriers to ion permeation in nanopores and channels

O Beckstein et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2004)

Review Biochemistry & Molecular Biology

How lipids affect the activities of integral membrane proteins

AG Lee

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES (2004)

Article Biochemistry & Molecular Biology

Low chemical specificity of the nicotinic acetylcholine receptor sterol activation site

GH Addona et al.

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES (2003)

Article Pharmacology & Pharmacy

Influence of membrane cholesterol on modulation of the GABAA receptor by neuroactive steroids and other potentiators

T Sooksawate et al.

BRITISH JOURNAL OF PHARMACOLOGY (2001)

Article Biochemistry & Molecular Biology

Effect of membrane lipid composition on the conformational equilibria of the nicotinic acetylcholine receptor

JE Baenziger et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2000)