Relative Positioning of Classical Benzodiazepines to the 纬2-Subunit of GABAA Receptors

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• 作者：Simon J. Middendorp ; Evelyn Hurni ; Matthias Sch枚nberger ; Marco Stein ; Michael Pangerl ; Dirk Trauner ; Erwin Sigel
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：August 15, 2014
• 年：2014
• 卷：9
• 期：8
• 页码：1846-1853
• 全文大小：351K
• ISSN：1554-8937

文摘

GABAb>Ab> receptors are the major inhibitory neurotransmitter receptors in the brain. Benzodiazepine exert their action via a high affinity-binding site at the 伪/纬 subunit interface on some of these receptors. Diazepam has sedative, hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects. It acts by potentiating the current evoked by the agonist GABA. Understanding specific interaction of benzodiazepines in the binding pocket of different GABAb>Ab> receptor isoforms might help to separate these divergent effects. As a first step, we characterized the interaction between diazepam and the major GABAb>Ab> receptor isoform 伪b>1b>尾b>2b>纬b>2b>. We mutated several amino acid residues on the 纬b>2b>-subunit assumed to be located near or in the benzodiazepine binding pocket individually to cysteine and studied the interaction with three ligands that are modified with a cysteine-reactive isothiocyanate group (-NCS). When the reactive NCS group is in apposition to the cysteine residue this leads to a covalent reaction. In this way, three amino acid residues, 纬b>2b>Tyr58, 纬b>2b>Asn60, and 纬b>2b>Val190 were located relative to classical benzodiazepines in their binding pocket on GABAb>Ab> receptors.