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

NEUROPHARMACOLOGY

卷:63

Article

Thompson, Andrew J.¹  Algazzaz, Mona¹  Ulens, Chris²  Lummis, Sarah C. R.¹ 

[1] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England

[2] Katholieke Univ Leuven, Lab Struct Neurobiol, Louvain, Belgium

关键词: Cys-loop;    Erwinia;    Ligand-gated;    Antagonist;    Nicotinic;    ELIC;    GLIC;    GABA;   

DOI  :  10.1016/j.neuropharm.2012.05.027

来源: Elsevier

【 摘 要 】

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 gamma-hydroxybutyric acid, which are weak agonists. A range of GABA(A) receptor non-competitive antagonists inhibit GABA-elicited ELIC responses including alpha-endosulfan (IC50 = 17 mu M), dieldrin (IC50 = 66 mu M), and picrotoxinin (IC50 = 96 mu 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 alpha-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 (IC50 > 100 mu 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. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

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