A novel GABAA receptor pharmacology: drugs interacting with the α+β‐ interface
GABAA receptors are ligand‐gated chloride channels composed of five subunits that can belong to different subunit classes. The existence of 19 different subunits gives rise to a multiplicity of GABAA receptor subtypes with distinct subunit composition; regional, cellular and subcellular distribution...
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Veröffentlicht in: | British journal of pharmacology 2012-05, Vol.166 (2), p.476-485 |
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description | GABAA receptors are ligand‐gated chloride channels composed of five subunits that can belong to different subunit classes. The existence of 19 different subunits gives rise to a multiplicity of GABAA receptor subtypes with distinct subunit composition; regional, cellular and subcellular distribution; and pharmacology. Most of these receptors are composed of two α, two β and one γ2 subunits. GABAA receptors are the site of action of a variety of pharmacologically and clinically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, anaesthetics and convulsants. Whereas GABA acts at the two extracellular β+α‐ interfaces of GABAA receptors, the allosteric modulatory benzodiazepines interact with the extracellular α+γ2‐ interface. In contrast, barbiturates, neuroactive steroids and anaesthetics seem to interact with solvent accessible pockets in the transmembrane domain. Several benzodiazepine site ligands have been identified that selectively interact with GABAA receptor subtypes containing α2βγ2, α3βγ2 or α5βγ2 subunits. This indicates that the different α subunit types present in these receptors convey sufficient structural differences to the benzodiazepine binding site to allow specific interaction with certain benzodiazepine site ligands. Recently, a novel drug binding site was identified at the α+β‐ interface. This binding site is homologous to the benzodiazepine binding site at the α+γ2‐ interface and is thus also strongly influenced by the type of α subunit present in the receptor. Drugs interacting with this binding site cannot directly activate but only allosterically modulate GABAA receptors. The possible importance of such drugs addressing a spectrum of receptor subtypes completely different from that of benzodiazepines is discussed. |
doi_str_mv | 10.1111/j.1476-5381.2011.01779.x |
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The existence of 19 different subunits gives rise to a multiplicity of GABAA receptor subtypes with distinct subunit composition; regional, cellular and subcellular distribution; and pharmacology. Most of these receptors are composed of two α, two β and one γ2 subunits. GABAA receptors are the site of action of a variety of pharmacologically and clinically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, anaesthetics and convulsants. Whereas GABA acts at the two extracellular β+α‐ interfaces of GABAA receptors, the allosteric modulatory benzodiazepines interact with the extracellular α+γ2‐ interface. In contrast, barbiturates, neuroactive steroids and anaesthetics seem to interact with solvent accessible pockets in the transmembrane domain. Several benzodiazepine site ligands have been identified that selectively interact with GABAA receptor subtypes containing α2βγ2, α3βγ2 or α5βγ2 subunits. This indicates that the different α subunit types present in these receptors convey sufficient structural differences to the benzodiazepine binding site to allow specific interaction with certain benzodiazepine site ligands. Recently, a novel drug binding site was identified at the α+β‐ interface. This binding site is homologous to the benzodiazepine binding site at the α+γ2‐ interface and is thus also strongly influenced by the type of α subunit present in the receptor. Drugs interacting with this binding site cannot directly activate but only allosterically modulate GABAA receptors. The possible importance of such drugs addressing a spectrum of receptor subtypes completely different from that of benzodiazepines is discussed.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/j.1476-5381.2011.01779.x</identifier><identifier>PMID: 22074382</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>allosteric binding sites ; anesthetics ; barbiturates ; benzodiazepines ; Biological and medical sciences ; CGS 9895 ; GABAA receptors ; Medical sciences ; pharmacology ; Pharmacology. Drug treatments ; receptor subtypes ; Reviews ; steroids ; structure</subject><ispartof>British journal of pharmacology, 2012-05, Vol.166 (2), p.476-485</ispartof><rights>2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society</rights><rights>2015 INIST-CNRS</rights><rights>2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417481/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417481/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27903,27904,45553,45554,46387,46811,53769,53771</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25826652$$DView record in Pascal Francis$$Hfree_for_read</backlink></links><search><creatorcontrib>Sieghart, Werner</creatorcontrib><creatorcontrib>Ramerstorfer, Joachim</creatorcontrib><creatorcontrib>Sarto‐Jackson, Isabella</creatorcontrib><creatorcontrib>Varagic, Zdravko</creatorcontrib><creatorcontrib>Ernst, Margot</creatorcontrib><title>A novel GABAA receptor pharmacology: drugs interacting with the α+β‐ interface</title><title>British journal of pharmacology</title><description>GABAA receptors are ligand‐gated chloride channels composed of five subunits that can belong to different subunit classes. The existence of 19 different subunits gives rise to a multiplicity of GABAA receptor subtypes with distinct subunit composition; regional, cellular and subcellular distribution; and pharmacology. Most of these receptors are composed of two α, two β and one γ2 subunits. GABAA receptors are the site of action of a variety of pharmacologically and clinically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, anaesthetics and convulsants. Whereas GABA acts at the two extracellular β+α‐ interfaces of GABAA receptors, the allosteric modulatory benzodiazepines interact with the extracellular α+γ2‐ interface. In contrast, barbiturates, neuroactive steroids and anaesthetics seem to interact with solvent accessible pockets in the transmembrane domain. Several benzodiazepine site ligands have been identified that selectively interact with GABAA receptor subtypes containing α2βγ2, α3βγ2 or α5βγ2 subunits. This indicates that the different α subunit types present in these receptors convey sufficient structural differences to the benzodiazepine binding site to allow specific interaction with certain benzodiazepine site ligands. Recently, a novel drug binding site was identified at the α+β‐ interface. This binding site is homologous to the benzodiazepine binding site at the α+γ2‐ interface and is thus also strongly influenced by the type of α subunit present in the receptor. Drugs interacting with this binding site cannot directly activate but only allosterically modulate GABAA receptors. The possible importance of such drugs addressing a spectrum of receptor subtypes completely different from that of benzodiazepines is discussed.</description><subject>allosteric binding sites</subject><subject>anesthetics</subject><subject>barbiturates</subject><subject>benzodiazepines</subject><subject>Biological and medical sciences</subject><subject>CGS 9895</subject><subject>GABAA receptors</subject><subject>Medical sciences</subject><subject>pharmacology</subject><subject>Pharmacology. 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Drug treatments</topic><topic>receptor subtypes</topic><topic>Reviews</topic><topic>steroids</topic><topic>structure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sieghart, Werner</creatorcontrib><creatorcontrib>Ramerstorfer, Joachim</creatorcontrib><creatorcontrib>Sarto‐Jackson, Isabella</creatorcontrib><creatorcontrib>Varagic, Zdravko</creatorcontrib><creatorcontrib>Ernst, Margot</creatorcontrib><collection>Pascal-Francis</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sieghart, Werner</au><au>Ramerstorfer, Joachim</au><au>Sarto‐Jackson, Isabella</au><au>Varagic, Zdravko</au><au>Ernst, Margot</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel GABAA receptor pharmacology: drugs interacting with the α+β‐ interface</atitle><jtitle>British journal of pharmacology</jtitle><date>2012-05</date><risdate>2012</risdate><volume>166</volume><issue>2</issue><spage>476</spage><epage>485</epage><pages>476-485</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>GABAA receptors are ligand‐gated chloride channels composed of five subunits that can belong to different subunit classes. The existence of 19 different subunits gives rise to a multiplicity of GABAA receptor subtypes with distinct subunit composition; regional, cellular and subcellular distribution; and pharmacology. Most of these receptors are composed of two α, two β and one γ2 subunits. GABAA receptors are the site of action of a variety of pharmacologically and clinically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, anaesthetics and convulsants. Whereas GABA acts at the two extracellular β+α‐ interfaces of GABAA receptors, the allosteric modulatory benzodiazepines interact with the extracellular α+γ2‐ interface. In contrast, barbiturates, neuroactive steroids and anaesthetics seem to interact with solvent accessible pockets in the transmembrane domain. Several benzodiazepine site ligands have been identified that selectively interact with GABAA receptor subtypes containing α2βγ2, α3βγ2 or α5βγ2 subunits. This indicates that the different α subunit types present in these receptors convey sufficient structural differences to the benzodiazepine binding site to allow specific interaction with certain benzodiazepine site ligands. Recently, a novel drug binding site was identified at the α+β‐ interface. This binding site is homologous to the benzodiazepine binding site at the α+γ2‐ interface and is thus also strongly influenced by the type of α subunit present in the receptor. Drugs interacting with this binding site cannot directly activate but only allosterically modulate GABAA receptors. The possible importance of such drugs addressing a spectrum of receptor subtypes completely different from that of benzodiazepines is discussed.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>22074382</pmid><doi>10.1111/j.1476-5381.2011.01779.x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | allosteric binding sites anesthetics barbiturates benzodiazepines Biological and medical sciences CGS 9895 GABAA receptors Medical sciences pharmacology Pharmacology. Drug treatments receptor subtypes Reviews steroids structure |
title | A novel GABAA receptor pharmacology: drugs interacting with the α+β‐ interface |
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