Ligand-Gated Channels

Barry, Peter H.; Lynch, Joseph W.

doi:10.1109/tnb.2004.842497

Cited by 41 publications

(29 citation statements)

References 60 publications

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“…They belong to the cysteine (Cys) loop ligand-gated ion channel (LGIC) superfamily and form pentamers of subunits, each of which consists of a N-terminal Cys loop-containing ligand-binding extracellular domain, four transmembrane helices and a C-terminus facing the extracellular space (Sine and Engel, 2006). Two vicinal cysteine residues in the extracellular domain, which are involved in acetylcholine (ACh) binding, define nAChR a subunits in all species, while non-a subunits (b, g, d or e) lack this motif (Ortells and Lunt, 1995;Le Novere and Changeux, 1995;Karlin, 2002;Connolly and Wafford, 2004;Barry and Lynch, 2005).…”

Section: Introductionmentioning

confidence: 99%

Differential sensitivity of Ctenocephalides felis and Drosophila melanogaster nicotinic acetylcholine receptor α1 and α2 subunits in recombinant hybrid receptors to nicotinoids and neonicotinoid insecticides

Dederer¹,

Werr²,

Ilg³

2011

Insect Biochemistry and Molecular Biology

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Section: Introductionmentioning

confidence: 99%

Differential sensitivity of Ctenocephalides felis and Drosophila melanogaster nicotinic acetylcholine receptor α1 and α2 subunits in recombinant hybrid receptors to nicotinoids and neonicotinoid insecticides

Dederer¹,

Werr²,

Ilg³

2011

Insect Biochemistry and Molecular Biology

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“…In this study, we directly investigated the influence of charged residues within the proposed MA stretch on functional properties of the ␣1 glycine receptor homomeric channels, a high conductance anionic Cys loop LGIC with well characterized ion permeation properties (4,18). Our results identify particular sets of basic residues affecting conductance, suggesting that the portals are indeed features of the extended glycine receptor permeation pathway.…”

mentioning

confidence: 99%

Characterization of the Effects of Charged Residues in the Intracellular Loop on Ion Permeation in α1 Glycine Receptor Channels

Carland

Cooper

Sugiharto

et al. 2009

Journal of Biological Chemistry

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The Cys loop receptor channels mediate fast synaptic transmission in the nervous system. The M2-demarcated transmembrane pore is an important determinant of their ion permeation properties. Portals within the intracellular domain are also part of the permeation pathway in cationic Cys loop receptors, with charged residues in a helical MA stretch partially lining these openings profoundly affecting channel conductance. It is unknown whether analogous portals contribute to the permeation pathway in anionic Cys loop receptors. We therefore investigated the influence of charged residues within the proposed MA stretch on functional properties of the homomeric glycine ␣1 receptor. Up to eight basic residues in the MA stretch were concurrently mutated to a negatively charged glutamate, and wild-type and mutant subunits were expressed in HEK-293 cells. Mutation of all eight residues produced a non-functional receptor. The greatest reduction in conductance at negative membrane potentials (from 92.2 ؎ 2.8 to 60.0 ؎ 2.2 picosiemens) was observed with glutamate present at the 377, 378, 385, and 386 positions (the 4E subunit). Inclusion of additional glutamate residues within this subunit did not decrease conductance further. Neutralizing these residues (the 4A subunit) caused a modest decrease in conductance (80.5 ؎ 2.3 picosiemens). Outward conductance at positive potentials was not markedly affected. Anion to cation selectivity and concentration-response relationships were unaffected by the 4A or 4E mutations. Our results identify basic residues affecting conductance in the glycine receptor, suggesting that portals are part of the extended permeation pathway but that the M2-demarcated channel pore is the dominant determinant of permeation properties in glycine receptors.Rapid and coordinated communication between neurons at synapses in the central nervous system is critical for the maintenance of normal brain function. Key to this process is the Cys loop superfamily of ligand-gated ion channels (LGICs), 4 which includes the cation-selective nicotinic acetylcholine (ACh) and 5-hydroxytryptamine type 3 (5-HT 3 ) and the anion-selective glycine and ␥-aminobutyric acid type A (GABA A ) receptors.LGICs convert the chemical messages conveyed by neurotransmitters into excitatory or inhibitory electrical signals via the selective conduction of ions. The polarity of the most permeant ion (ion charge selectivity) and the rate at which the ions permeate (the single channel conductance, ␥) are major determinants of how this synaptic signal affects neuronal excitability.Cys loop LGICs are composed of five protein subunits arranged around a central ion-conducting channel pore. Each of the five subunits consists of a large extracellular domain harboring the neurotransmitter binding site, four membranespanning domains (M1-M4) and, in mammalian LGICs at least, a large intracellular loop connecting M3-M4. The electron microscopic images of the Torpedo marmorata nicotinic ACh receptor (1-3) provide our most complete picture of the structure...

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“…Like other members of the cysteine-loop ligand-gated ion channel (LGIC) family, functional GlyRs comprise 5 subunits arranged symmetrically around a central ion-conducting pore. Each subunit consists of a large extracellular ligand-binding domain followed by 4 ␣-helical transmembrane domains, termed M1-M4 (3,4).…”

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confidence: 99%

A Picrotoxin-specific Conformational Change in the Glycine Receptor M2–M3 Loop

Hawthorne

Lynch

2005

Journal of Biological Chemistry

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The external loop linking the M2 and M3 transmembrane domains is crucial for coupling agonist binding to channel gating in the glycine receptor chloride channel (GlyR). A substituted cysteine accessibility scan previously showed that glycine activation increased the surface accessibility of 6 contiguous residues (Arg 271 -Lys 276 ) toward the N-terminal end of the homomeric ␣1 GlyR M2-M3 loop. In the present study we used a similar approach to determine whether the allosteric antagonist, picrotoxin, could impose conformational changes to this domain that cannot be induced by varying agonist concentrations alone. Picrotoxin slowed the reaction rate of a sulfhydryl-containing compound (MTSET) with A272C, S273C, and L274C. Before interpreting this as a picrotoxin-specific conformational change, it was necessary to eliminate the possibility of steric competition between picrotoxin and MTSET. Accordingly, we showed that picrotoxin and the structurally unrelated blocker, bilobalide, were both trapped in the R271C GlyR in the closed state and that a point mutation to the pore-lining Thr 6 residue abolished inhibition by both compounds. We also demonstrated that the picrotoxin dissociation rate was linearly related to the channel open probability. These observations constitute a strong case for picrotoxin binding in the pore. We thus conclude that the picrotoxin-specific effects on the M2-M3 loop are mediated allosterically. This suggests that the M2-M3 loop responds differently to the occupation of different binding sites.

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Ligand-Gated Channels

Cited by 41 publications

References 60 publications

Differential sensitivity of Ctenocephalides felis and Drosophila melanogaster nicotinic acetylcholine receptor α1 and α2 subunits in recombinant hybrid receptors to nicotinoids and neonicotinoid insecticides

Differential sensitivity of Ctenocephalides felis and Drosophila melanogaster nicotinic acetylcholine receptor α1 and α2 subunits in recombinant hybrid receptors to nicotinoids and neonicotinoid insecticides

Characterization of the Effects of Charged Residues in the Intracellular Loop on Ion Permeation in α1 Glycine Receptor Channels

A Picrotoxin-specific Conformational Change in the Glycine Receptor M2–M3 Loop

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