Query: Ligand gated ion channels receptor

title: Emerging Molecular Mechanisms of Signal Transduction in Pentameric Ligand Gated Ion Channels
abstract: Nicotinic acetylcholine, serotonin type 3, g amminobutyric acid type A, and glycine receptors are major players of human neuronal communication. They belong to the family of pentameric ligand gated ion channels, sharing a highly conserved modular 3D structure. Recently, high resolution structures of both open and closed pore conformations have been solved for a bacterial, an invertebrate, and a vertebrate receptor in this family. These data suggest that a common gating mechanism occurs, coupling neurotransmitter binding to pore opening, but they also pinpoint significant differences among subtypes. In this Review, we summarize the structural and functional data in light of these gating models and speculate about their mechanistic consequences on ion permeation, pathological mutations, as well as functional regulation by orthosteric and allosteric effectors.

title: Phylogenetic conservation of protein lipid motifs in pentameric ligand gated ion channels.
abstract: Using the crosstalk between the nicotinic acetylcholine receptor (nAChR) and its lipid microenvironment as a paradigm, this short overview analyzes the occurrence of structural motifs which appear not only to be conserved within the nAChR family and contemporary eukaryotic members of the pentameric ligand gated ion channel (pLGIC) superfamily, but also extend to prokaryotic homologues found in bacteria. The evolutionarily conserved design is manifested in: 1) the concentric three ring architecture of the transmembrane region, 2) the occurrence in this region of distinct lipid consensus motifs in prokaryotic and eukaryotic pLGIC and 3) the key participation of the outer TM4 ring in conveying the influence of the lipid membrane environment to the middle TM1 TM3 ring and this, in turn, to the inner TM2 channel lining ring, which determines the ion selectivity of the channel. The preservation of these constant structural functional features throughout such a long phylogenetic span likely points to the successful gain of function conferred by their early acquisition. This article is part of a Special Issue entitled: Lipid protein interactions.

title: Structural Comparisons of Ligand gated Ion Channels in Open, Closed, and Desensitized States Identify a Novel Propofol binding Site on Mammalian &ggr; Aminobutyric Acid Type A Receptors
abstract: Most anesthetics, particularly intravenous agents such as propofol and etomidate, enhance the actions of the neurotransmitter &ggr; aminobutyric acid (GABA) at the GABA type A receptor. However, there is no agreement as where anesthetics bind to the receptor. A novel approach would be to identify regions on the receptor that are state dependent, which would account for the ability of anesthetics to affect channel opening by binding differentially to the open and closed states. The open and closed structures of the GABA type A receptor homologues Gloeobacter ligand gated ion channel and glutamate gated chloride channel were compared, and regions in the channels that move on channel opening and closing were identified. Docking calculations were performed to investigate possible binding of propofol to the GABA type A &bgr;3 homomer in this region. A comparison between the open and closed states of the Gloeobacter ligand gated ion channel and glutamate gated chloride channel channels identified a region at the top of transmembrane domains 2 and 3 that shows maximum movement when the channels transition between the open and closed states. Docking of propofol into the GABA type A &bgr;3 homomer identified two putative binding cavities in this same region, one with a high affinity and one with a lower affinity. Both cavities were adjacent to a histidine residue that has been photolabeled by a propofol analog, and both sites would be disrupted on channel closing. These calculations support the conclusion of a recent photolabeling study that propofol acts at a site at the interface between the extracellular and transmembrane domains, close to the top of transmembrane domain 2.

title: Insect olfactory receptors are heteromeric ligand gated ion channels
abstract: In insects, each olfactory sensory neuron expresses between one and three ligand binding members of the olfactory receptor (OR) gene family, along with the highly conserved and broadly expressed Or83b co receptor. The functional insect OR consists of a heteromeric complex of unknown stoichiometry but comprising at least one variable odorant binding subunit and one constant Or83b family subunit. Insect ORs lack homology to G protein coupled chemosensory receptors in vertebrates and possess a distinct seven transmembrane topology with the amino terminus located intracellularly. Here we provide evidence that heteromeric insect ORs comprise a new class of ligand activated non selective cation channels. Heterologous cells expressing silkmoth, fruitfly or mosquito heteromeric OR complexes showed extracellular Ca2+ influx and cation non selective ion conductance on stimulation with odorant. Odour evoked OR currents are independent of known G protein coupled second messenger pathways. The fast response kinetics and OR subunit dependent K+ ion selectivity of the insect OR complex support the hypothesis that the complex between OR and Or83b itself confers channel activity. Direct evidence for odorant gated channels was obtained by outside out patch clamp recording of Xenopus oocyte and HEK293T cell membranes expressing insect OR complexes. The ligand gated ion channel formed by an insect OR complex seems to be the basis for a unique strategy that insects have acquired to respond to the olfactory environment.

title: A nomenclature for ligand gated ion channels
abstract: The ligand gated ion channels that participate in fast synaptic transmission comprise the nicotinic acetylcholine, 5 hydroxytryptamine3 (5 HT3) gamma aminobutyric acidA (GABA(A) glycine, ionotropic glutamate and P2X receptor families. A consistent and systematic nomenclature for the individual subunits that comprise these receptors and the receptors that result from their co assembly is highly desirable. There is also a need to develop criteria that aid in deciding which of the vast number of heteromeric combinations of subunits that can be assembled in heterologous expression systems in vitro, are known, or likely, to exist as functional receptors in vivo. The aim of this short article is to summarize the progress being made by the nomenclature committee of IUPHAR (NC IUPHAR) in formulating recommendations that attempt to address these issues.

title: The Role of Intracellular Linkers in Gating and Desensitization of Human Pentameric Ligand Gated Ion Channels
abstract: It has recently been proposed that post translational modification of not only the M3 M4 linker but also the M1 M2 linker of pentameric ligand gated ion channels modulates function in vivo. To estimate the involvement of the M1 M2 linker in gating and desensitization, we engineered a series of mutations to this linker of the human adult muscle acetylcholine receptor (AChR) the a3b4 AChR and the homomeric a1 glycine receptor (GlyR) All tested M1 M2 linker mutations had little effect on the kinetics of deactivation or desensitization compared with the effects of mutations to the M2 a helix or the extracellular M2 M3 linker. However, when the effects of mutations were assessed with 50 Hz trains of ~1 ms pulses of saturating neurotransmitter, some mutations led to much more, and others to much less, peak current depression than observed for the wild type channels, suggesting that these mutations could affect the fidelity of fast synaptic transmission. Nevertheless, no mutation to this linker could mimic the irreversible loss of responsiveness reported to result from the oxidation of the M1 M2 linker cysteines of the a3 AChR subunit. We also replaced the M3 M4 linker of the a1 GlyR with much shorter peptides and found that none of these extensive changes affects channel deactivation strongly or reduces the marked variability in desensitization kinetics that characterizes the wild type channel. However, we found that these large mutations to the M3 M4 linker can have pronounced effects on desensitization kinetics, supporting the notion that its post translational modification could indeed modulate a1 GlyR behavior.

title: Allosteric modulation of ligand gated ion channels by ivermectin.
abstract: Ivermectin acts as a positive allosteric regulator of several ligand gated channels including the glutamate gated chloride channel (GluCl) gamma aminobutyric acid type A receptor, glycine receptor, neuronal alpha7 nicotinic receptor and purinergic P2X4 receptor. In most of the ivermectin sensitive channels, the effects of ivermectin include the potentiation of agonist induced currents at low concentrations and channel opening at higher concentrations. Based on mutagenesis, electrophysiological recordings and functional analysis of chimeras between ivermectin sensitive and ivermectin insensitive receptors, it has been concluded that ivermectin acts by insertion between transmembrane helices. The three dimensional structure of C. elegans GluCl complexed with ivermectin has revealed the details of the ivermectin binding site, however, no generic motif of amino acids could accurately predict ivermectin binding site for other ligand gated channels. Here, we will review what is currently known about ivermectin binding and modulation of Cys loop receptor family of ligand gated ion channels and what are the critical structural determinants underlying potentiation of the P2X4 receptor channel.

title: Intramembrane Aromatic Interactions Influence the Lipid Sensitivities of Pentameric Ligand gated Ion Channels*
abstract: Channel gating is uncoupled from agonist binding when nicotinic receptors lack activating lipids.  Gating is also uncoupled with ELIC, but engineered aromatic interactions at the M4 M1/M3 interface restore coupling.  The strength of M4 M1/M3 interactions impacts both coupling and lipid sensitivity.  Variable levels of intramembrane aromatics in eukaryotic homologs likely lead to variable lipid sensitivities. Although the Torpedo nicotinic acetylcholine receptor (nAChR) reconstituted into phosphatidylcholine (PC) membranes lacking cholesterol and anionic lipids adopts a conformation where agonist binding is uncoupled from channel gating, the underlying mechanism remains to be defined. Here, we examine the mechanism behind lipid dependent uncoupling by comparing the propensities of two prokaryotic homologs, Gloebacter and Erwinia ligand gated ion channel (GLIC and ELIC, respectively) to adopt a similar uncoupled conformation. Membrane reconstituted GLIC and ELIC both exhibit folded structures in the minimal PC membranes that stabilize an uncoupled nAChR. GLIC, with a large number of aromatic interactions at the interface between the outermost transmembrane a helix, M4, and the adjacent transmembrane a helices, M1 and M3, retains the ability to flux cations in this uncoupling PC membrane environment. In contrast, ELIC, with a level of aromatic interactions intermediate between that of the nAChR and GLIC, does not undergo agonist induced channel gating, although it does not exhibit the expected biophysical characteristics of the uncoupled state. Engineering new aromatic interactions at the M4 M1/M3 interface to promote effective M4 interactions with M1/M3, however, increases the stability of the transmembrane domain to restore channel function. Our data provide direct evidence that M4 interactions with M1/M3 are modulated during lipid sensing. Aromatic residues strengthen M4 interactions with M1/M3 to reduce the sensitivities of pentameric ligand gated ion channels to their surrounding membrane environment.

title: New structural motif for ligand gated ion channels defined by an ionotropic ATP receptor
abstract: THE adenosine 5' triphosphate (ATP) molecule is an extracellular messenger in neural and non neural tissues, where it activates several cell surface receptor subtypes, including G protein coupled receptors and ligand gated ion channels1. ATP gated channels (termed P2X receptors) have been characterized on smooth muscle cells and autonomic and sensory neurons, where they mediate membrane depolarization and, in some cases, Ca2+ entry2. P2x receptors are functionally heterogeneous, but resemble acetylcholine and serotonin gated channels with respect to ion selectivity and kinetic parameters of channel gating. We report here that despite such close functional similarities, the deduced sequence of a cloned P2x receptor predicts an unusual subunit structure resembling voltage insensitive cation channels. Thus, the P2x receptor provides a striking example of convergent evolution, whereby proteins have been fashioned with similar functional properties from subunits having very different structural characteristics. There is sequence similarity between the ATP receptor and RP 2, a gene activated in thymocytes undergoing programmed cell death3. RP 2 may encode a receptor for ATP or another metabolite released during apoptosis.

title: The Cys loop superfamily of ligand gated ion channels: the impact of receptor structure on function.
abstract: The Cys loop receptors constitute an important superfamily of LGICs (ligand gated ion channels) comprising receptors for acetylcholine, 5 HT3 (5 hydroxytryptamine; 5 HT3 receptors) glycine and GABA (gamma aminobutyric acid; GABAA receptors) A vast knowledge of the structure of the Cys loop superfamily and its impact on channel function have been accrued over the last few years, leading to exciting new proposals on how ion channels open and close in response to agonist binding. Channel opening is initiated by the extracellular association of agonists to discrete binding pockets, leading to dramatic conformational changes, culminating in the opening of a central ion pore. The importance of channel structure is exemplified in the allosteric modulation of channel function by the binding of other molecules to distinct sites on the channel, which exerts an additional level of control on their function. The subsequent conformational changes (gating) lead to channel opening and ion transport. Following channel pore opening, ion selectivity is determined by receptor structure in, and around, the ion pore. As a final level of control, cytoplasmic determinants control the magnitude (conductance) of ion flow into the cell. Thus the Cys loop receptors are complex molecular motors, with moving parts, which can transduce extracellular signals across the plasma membrane. Once the full mechanical motions involved are understood, it may be possible to design sophisticated therapeutic agents to modulate their activity, or at least be able to throw a molecular spanner into the works!