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gaba-a activated ligand gated ion channels

Jay Spampanato, Anne Gibson, F Edward Dudek
Macrocyclic lactones (MLs) are commonly used treatments for parasitic worm and insect infections in humans, livestock and companion animals. MLs target the invertebrate glutamate-activated chloride channel that is not present in vertebrates. MLs are not entirely inert in vertebrates though; they have been reported to have activity in heterologous expression systems consisting of ligand-gated ion channels that are present in the mammalian central nervous system (CNS). However, these compounds are typically not able to reach significant concentrations in the CNS due to the activity of the blood-brain barrier P-glycoprotein extrusion system...
January 24, 2018: Journal of Neurophysiology
Jennina Taylor-Wells, Anish Senan, Isabel Bermudez, Andrew K Jones
The insect GABA receptor, RDL, is the target of several classes of pesticides. The peptide sequences of RDL are generally highly conserved between diverse insects. However, RNA A-to-I editing can effectively alter amino acid residues of RDL in a species specific manner, which can affect the potency of GABA and possibly insecticides. We report here that RNA A-to-I editing alters the gene products of Rdl in three mosquito disease vectors, recoding five amino acid residues in RDL of Aedes aegypti and six residues in RDLs of Anopheles gambiae and Culex pipiens, which is the highest extent of editing in RDL observed to date...
February 2018: Insect Biochemistry and Molecular Biology
Marco Treven, David C B Siebert, Raphael Holzinger, Konstantina Bampali, Jure Fabjan, Zdravko Varagic, Laurin Wimmer, Friederike Steudle, Petra Scholze, Michael Schnürch, Marko D Mihovilovic, Margot Ernst
BACKGROUND AND PURPOSE: The GABAA receptors are ligand-gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular α+/β- interfaces, using a systematically varied series of pyrazoloquinolinones. EXPERIMENTAL APPROACH: Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA-elicited currents by the newly synthesized and reference compounds were investigated by the two-electrode voltage clamp method...
February 2018: British Journal of Pharmacology
Flóra Gölöncsér, Mária Baranyi, Diána Balázsfi, Kornél Demeter, József Haller, Tamás F F Freund, Dóra Zelena, Beáta Sperlágh
Serotonergic and glutamatergic neurons of median raphe region (MRR) play a pivotal role in the modulation of affective and cognitive functions. These neurons synapse both onto themselves and remote cortical areas. P2X7 receptors ( P2rx7 ) are ligand gated ion channels expressed by central presynaptic excitatory nerve terminals and involved in the regulation of neurotransmitter release. P2rx7 s are implicated in various neuropsychiatric conditions such as schizophrenia and depression. Here we investigated whether 5-HT release released from the hippocampal terminals of MRR is subject to modulation by P2rx7 s...
2017: Frontiers in Molecular Neuroscience
Christine L Dixon, Pankaj Sah, Angelo Keramidas, Joseph W Lynch, Nela Durisic
GABA-A receptors (GABAARs) are pentameric ligand-gated ion channels that are assembled mainly from α (α1-6), β (β1-3) and γ (γ1-3) subunits. Although GABAARs containing γ2L subunits mediate most of the inhibitory neurotransmission in the brain, significant expression of γ1 subunits is seen in the amygdala, pallidum and substantia nigra. However, the location and function of γ1-containing GABAARs in these regions remains unclear. In "artificial" synapses, where the subunit composition of postsynaptic receptors is specifically controlled, γ1 incorporation slows the synaptic current decay rate without affecting channel deactivation, suggesting that γ1-containing receptors are not clustered and therefore activated by diffuse neurotransmitter...
2017: Frontiers in Molecular Neuroscience
J P Daniel Therien, John E Baenziger
Although transmembrane helix-helix interactions must be strong enough to drive folding, they must still permit the inter-helix movements associated with conformational change. Interactions between the outermost M4 and adjacent M1 and M3 α-helices of pentameric ligand-gated ion channels have been implicated in folding and function. Here, we evaluate the role of different physical interactions at this interface in the function of two prokaryotic homologs, GLIC and ELIC. Strikingly, disruption of most interactions in GLIC lead to either a reduction or a complete loss of expression and/or function, while analogous disruptions in ELIC often lead to gains in function...
March 27, 2017: Scientific Reports
Moawiah M Naffaa, Sandy Hung, Mary Chebib, Graham A R Johnston, Jane R Hanrahan
The homomeric GABA-ρ ligand-gated ion channels (also known as GABAC or GABAA -ρ receptors) are similar to heteromeric GABAA receptors in structure, function and mechanism of action. However, their distinctive pharmacological properties and distribution make them of special interest. This review focuses on GABA-ρ ion channel structure, ligand selectivity toward ρ receptors over heteromeric GABAA receptor sub-types and selectivity between different homomeric ρ sub-type receptors. Several GABA analogues show selectivity at homomeric GABA-ρ receptors over heteromeric GABAA receptors...
July 2017: British Journal of Pharmacology
Jean-Philippe Pin, Bernhard Bettler
The neurotransmitters glutamate and γ-aminobutyric acid (GABA) transmit synaptic signals by activating fast-acting ligand-gated ion channels and more slowly acting G-protein-coupled receptors (GPCRs). The GPCRs for these neurotransmitters, metabotropic glutamate (mGlu) and GABAB receptors, are atypical GPCRs with a large extracellular domain and a mandatory dimeric structure. Recent studies have revealed how these receptors are activated through multiple allosteric interactions between subunit domains. It emerges that the molecular complexity of these receptors is further increased through association with trafficking, effector and regulatory proteins...
December 1, 2016: Nature
Sergio Valbuena, Juan Lerma
Neurotransmitter receptors are responsible for the transfer of information across the synapse. While ionotropic receptors form ion channels and mediate rapid membrane depolarization, so-called metabotropic receptors exert their action though slower, less direct intracellular signaling pathways. Glutamate, GABA, and acetylcholine can activate both ionotropic and metabotropic receptors, yet the distinction between these "canonical" signaling systems has become less clear since ionotropic receptors were proposed to also activate second messenger systems, defining a "non-canonical" signaling pathway...
October 19, 2016: Neuron
Mona A Alqazzaz, Kerry L Price, Sarah C R Lummis
Cys-loop receptors play important roles in signal transduction in multicellular organisms, but similar proteins exist in prokaryotes, the best studied of which is the Gloeobacter ligand-gated ion channel (GLIC). GLIC is activated by protons with 50% activation (pH50) at pH 5.5, and while a histidine residue in its pore-forming α-helix (M2) is known to be involved in gating, there is also evidence of a proton-sensitive region in the extracellular domain. However, this proton-sensitive region does not appear to be located in the region of GLIC equivalent to the agonist binding site in related proteins...
October 14, 2016: Biochemistry
Federico Comitani, Vittorio Limongelli, Carla Molteni
Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop superfamily are important neuroreceptors that mediate fast synaptic transmission. They are activated by the binding of a neurotransmitter, but the details of this process are still not fully understood. As a prototypical pLGIC, here we choose the insect resistance to dieldrin (RDL) receptor involved in resistance to insecticides and investigate the binding of the neurotransmitter GABA to its extracellular domain at the atomistic level. We achieve this by means of μ-sec funnel-metadynamics simulations, which efficiently enhance the sampling of bound and unbound states by using a funnel-shaped restraining potential to limit the exploration in the solvent...
July 12, 2016: Journal of Chemical Theory and Computation
Xiaojun Xu, Caraline Sepich, Ronald J Lukas, Guonian Zhu, Yongchang Chang
Avermectins are a group of compounds isolated from a soil-dwelling bacterium. They have been widely used as parasiticides and insecticides, acting by relatively irreversible activation of invertebrate chloride channels. Emamectin is a soluble derivative of an avermectin. It is an insecticide, which persistently activates glutamate-gated chloride channels. However, its effects on mammalian ligand-gated ion channels are unknown. To this end, we tested the effect of emamectin on two cation selective nicotinic receptors and two GABA-gated chloride channels expressed in Xenopus oocytes using two-electrode voltage clamp...
May 13, 2016: Biochemical and Biophysical Research Communications
Frédéric Knoflach, Maria-Clemencia Hernandez, Daniel Bertrand
GABAA receptors are ligand-gated ion channels that form a fundamental component of inhibitory neurotransmission in the central and peripheral nervous systems. However, since the initial recordings of inhibitory electrical activity of neurons in response to GABA, these receptors have been found to play a more complex role and can, under some circumstances, function in an excitatory manner. This has been demonstrated via electrophysiological recordings conducted in both mature and developing neurons from different brain regions, as well as in various subcellular locations such as dendritic and axonal membranes...
September 1, 2016: Biochemical Pharmacology
Eveline Wijckmans, Mieke Nys, Sarah Debaveye, Marijke Brams, Els Pardon, Katrien Willegems, Daniel Bertrand, Jan Steyaert, Rouslan Efremov, Chris Ulens
Cys-loop receptors are membrane spanning ligand-gated ion channels involved in fast excitatory and inhibitory neurotransmission. Three-dimensional structures of these ion channels, determined by X-ray crystallography or electron microscopy, have revealed valuable information regarding the molecular mechanisms underlying ligand recognition, channel gating and ion conductance. To extend and validate the current insights, we here present promising candidates for further structural studies. We report the biochemical and functional characterization of Cys-loop receptor homologues identified in the proteome of Alvinella pompejana, an extremophilic, polychaete annelid found in hydrothermal vents at the bottom of the Pacific Ocean...
2016: PloS One
Agenor Limon, Argel Estrada-Mondragón, Jorge M Reyes Ruiz, Ricardo Miledi
Dipicrylamine (DPA) is a commonly used acceptor agent in Förster resonance energy transfer experiments that allows the study of high-frequency neuronal activity in the optical monitoring of voltage in living cells. However, DPA potently antagonizes GABAA receptors that contain α1 and β2 subunits by a mechanism which is not clearly understood. In this work, we aimed to determine whether DPA modulation is a general phenomenon of Cys-loop ligand-gated ion channels (LGICs), and whether this modulation depends on particular amino acid residues...
April 2016: Molecular Pharmacology
Moawiah M Naffaa, Mary Chebib, David E Hibbs, Jane R Hanrahan
Five sets of ρ1 GABAC homology models were generated based on X-ray crystal structures of the acetylcholine binding protein (AChBP), the ion channel from Caenorhabditis elegans (GLIC), the ion channel from Erwinia chrysanthemi (ELIC), the homomeric GABAA β3 ion channel, and the homomeric α-subunit of glutamate-gated homopentameric chloride channel (GluCl). The GluCl based model was found to the represent the structure of ρ1 GABAC receptors. The GABA pose docked in the selected best model was confirmed by QM-polarized ligand docking and induced fit docking protocol, and used to study molecular interactions in the ρ1 GABA binding site...
November 2015: Journal of Molecular Graphics & Modelling
Paul Hoerbelt, Tara A Lindsley, Mark W Fleck
Dopamine is a critical neuromodulator that activates GPCRs in mammals or ligand-gated ion channels in invertebrates. The present study demonstrates that dopamine (0.1-10 mm) exerts novel, opposing effects on different populations of mammalian (rat) GABAA receptors. Using whole-cell patch-clamp electrophysiology, we observed direct dopamine-mediated inhibition of tonic-level (1 μm) GABA-evoked currents in untransfected striatal neurons that could be recapitulated in HEK293 cells containing α1β3 or α1β2γ2 subunits...
February 25, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Saad Hannan, Martin Mortensen, Trevor G Smart
The snake neurotoxin α-bungarotoxin (α-Bgtx) is a competitive antagonist at nicotinic acetylcholine receptors (nAChRs) and is widely used to study their function and cell-surface expression. Increasingly, α-Bgtx is also used as an imaging tool for fluorophore-labelling studies, and given the structural conservation within the pentameric ligand-gated ion channel family, we assessed whether α-Bgtx could bind to recombinant and native γ-aminobutyric type-A receptors (GABAARs). Applying fluorophore-linked α-Bgtx to recombinant αxβ1/2γ2 GABAARs expressed in HEK-293 cells enabled clear cell-surface labelling of α2β1/2γ2 contrasting with the weaker staining of α1/4β1/2γ2, and no labelling for α3/5/6β1/2γ2...
June 2015: Neuropharmacology
Werner Sieghart
GABAA receptors are ligand-gated ion channels composed of five subunits that can be opened by GABA and be modulated by multiple pharmacologically and clinically important drugs. Over the time, hundreds of compounds from different structural classes have been demonstrated to modulate, directly activate, or inhibit GABAA receptors, and most of these compounds interact with more than one binding site at these receptors. Crystal structures of proteins and receptors homologous to GABAA receptors as well as homology modeling studies have provided insights into the possible location of ligand interaction sites...
2015: Advances in Pharmacology
Nicholas P Franks
BACKGROUND: Most anesthetics, particularly intravenous agents such as propofol and etomidate, enhance the actions of the neurotransmitter γ-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...
April 2015: Anesthesiology
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