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The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor.

ABSTRACT: The Erwinia ligand-gated ion channel (ELIC) is a bacterial homologue of vertebrate Cys-loop ligand-gated ion channels. It is activated by GABA, and this property, combined with its structural similarity to GABA(A) and other Cys-loop receptors, makes it potentially an excellent model to probe their structure and function. Here we characterise the pharmacological profile of ELIC, examining the effects of compounds that could activate or inhibit the receptor. We confirm that a range of amino acids and classic GABA(A) receptor agonists do not elicit responses in ELIC, and we show the receptor can be at least partially activated by 5-aminovaleric acid and ?-hydroxybutyric acid, which are weak agonists. A range of GABA(A) receptor non-competitive antagonists inhibit GABA-elicited ELIC responses including ?-endosulfan (IC?? = 17 ?M), dieldrin (IC?? = 66 ?M), and picrotoxinin (IC?? = 96 ?M) which were the most potent. Docking suggested possible interactions at the 2' and 6' pore-lining residues, and mutagenesis of these residues supports this hypothesis for ?-endosulfan. A selection of compounds that act at Cys-loop and other receptors also showed some efficacy at blocking ELIC responses, but most were of low potency (IC?? > 100 ?M). Overall our data show that a number of compounds can inhibit ELIC, but it has limited pharmacological similarity to GLIC and to Cys-loop receptors.

SUBMITTER: Thompson AJ

PROVIDER: S-EPMC3430861 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor.

Thompson Andrew J AJ Alqazzaz Mona M Ulens Chris C Lummis Sarah C R SC

Neuropharmacology 20120604 4

The Erwinia ligand-gated ion channel (ELIC) is a bacterial homologue of vertebrate Cys-loop ligand-gated ion channels. It is activated by GABA, and this property, combined with its structural similarity to GABA(A) and other Cys-loop receptors, makes it potentially an excellent model to probe their structure and function. Here we characterise the pharmacological profile of ELIC, examining the effects of compounds that could activate or inhibit the receptor. We confirm that a range of amino acids ...[more]

PMID: 22677470

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Project description:Prokaryotic channels, such as Erwinia chrysanthemi ligand-gated ion channel (ELIC) and Gloeobacter violaceus ligand-gated ion channel, give key structural information for the pentameric ligand-gated ion channel family, which includes nicotinic acetylcholine receptors. ELIC, a cationic channel from E. chrysanthemi, is particularly suitable for single-channel recording because of its high conductance. Here, we report on the kinetic properties of ELIC channels expressed in human embryonic kidney 293 cells. Single-channel currents elicited by the full agonist propylamine (0.5-50 mM) in outside-out patches at -60 mV were analyzed by direct maximum likelihood fitting of kinetic schemes to the idealized data. Several mechanisms were tested, and their adequacy was judged by comparing the predictions of the best fit obtained with the observable features of the experimental data. These included open-/shut-time distributions and the time course of macroscopic propylamine-activated currents elicited by fast theta-tube applications (50-600 ms, 1-50 mM, -100 mV). Related eukaryotic channels, such as glycine and nicotinic receptors, when fully liganded open with high efficacy to a single open state, reached via a preopening intermediate. The simplest adequate description of their activation, the "Flip" model, assumes a concerted transition to a single intermediate state at high agonist concentration. In contrast, ELIC open-time distributions at saturating propylamine showed multiple components. Thus, more than one open state must be accessible to the fully liganded channel. The "Primed" model allows opening from multiple fully liganded intermediates. The best fits of this type of model showed that ELIC maximum open probability (99%) is reached when at least two and probably three molecules of agonist have bound to the channel. The overall efficacy with which the fully liganded channel opens was ? 102 (? 20 for ?1? glycine channels). The microscopic affinity for the agonist increased as the channel activated, from 7 mM for the resting state to 0.15 mM for the partially activated intermediate state.

Dataset Information

The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor.

Publications

The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor.

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