Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors
A cDNA encoding the human gamma-aminobutyric acidA (GABAA) receptor alpha 6 subunit has been cloned and sequenced. The deduced amino acid sequence of this cDNA shows 91.4% identity with the published rat alpha 6 subunit. In situ hybridization histochemistry reveals the alpha 6 mRNA to be located wit...
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| Veröffentlicht in: | Molecular pharmacology 1996-02, Vol.49 (2), p.253-259 |
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| creator | Hadingham, K L Garrett, E M Wafford, K A Bain, C Heavens, R P Sirinathsinghji, D J Whiting, P J |
| description | A cDNA encoding the human gamma-aminobutyric acidA (GABAA) receptor alpha 6 subunit has been cloned and sequenced. The deduced
amino acid sequence of this cDNA shows 91.4% identity with the published rat alpha 6 subunit. In situ hybridization histochemistry
reveals the alpha 6 mRNA to be located within the granule cell layer of the human cerebellar cortex. Recombinant human alpha
6 beta gamma 2S GABAA receptors have been expressed in both stably transfected cells and Xenopus oocytes, and the pharmacology
of the benzodiazepine binding site has been determined. The recombinant receptor has a diazepam-insensitive pharmacology,
with negligible affinity for a number of classic benzodiazepines. A number of compounds that bind to the benzodiazepine site
potentiated the GABA response of alpha 6 beta 2 gamma 2 receptors. Most importantly, the classic benzodiazepine antagonist
ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788) and the partial
inverse agonist ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-4513)
both acted as agonists at the alpha 6 containing receptor. This observation demonstrates definitively that efficacy of benzodiazepine
compounds cannot be generalized across receptor subtypes and may also help explain some of the behavioral effects that have
been reported for these compounds. |
| format | Article |
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amino acid sequence of this cDNA shows 91.4% identity with the published rat alpha 6 subunit. In situ hybridization histochemistry
reveals the alpha 6 mRNA to be located within the granule cell layer of the human cerebellar cortex. Recombinant human alpha
6 beta gamma 2S GABAA receptors have been expressed in both stably transfected cells and Xenopus oocytes, and the pharmacology
of the benzodiazepine binding site has been determined. The recombinant receptor has a diazepam-insensitive pharmacology,
with negligible affinity for a number of classic benzodiazepines. A number of compounds that bind to the benzodiazepine site
potentiated the GABA response of alpha 6 beta 2 gamma 2 receptors. Most importantly, the classic benzodiazepine antagonist
ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788) and the partial
inverse agonist ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-4513)
both acted as agonists at the alpha 6 containing receptor. This observation demonstrates definitively that efficacy of benzodiazepine
compounds cannot be generalized across receptor subtypes and may also help explain some of the behavioral effects that have
been reported for these compounds.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 8632757</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Amino Acid Sequence ; Animals ; Antisense Elements (Genetics) ; Autoradiography ; Base Sequence ; Cerebellar Cortex - metabolism ; Cloning, Molecular ; DNA Primers ; DNA, Complementary ; Female ; Flunitrazepam - pharmacology ; gamma-Aminobutyric Acid - pharmacology ; Humans ; In Situ Hybridization ; Kinetics ; L Cells (Cell Line) ; Ligands ; Macromolecular Substances ; Membrane Potentials - drug effects ; Mice ; Molecular Sequence Data ; Oocytes - drug effects ; Oocytes - physiology ; Pentobarbital - pharmacology ; Polymerase Chain Reaction ; Pregnanolone - pharmacology ; Rats ; Receptors, GABA-A - biosynthesis ; Receptors, GABA-A - chemistry ; Receptors, GABA-A - physiology ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - chemistry ; Recombinant Proteins - metabolism ; RNA, Messenger - analysis ; RNA, Messenger - biosynthesis ; Sequence Homology, Amino Acid ; Transfection ; Xenopus ; Xenopus laevis</subject><ispartof>Molecular pharmacology, 1996-02, Vol.49 (2), p.253-259</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8632757$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hadingham, K L</creatorcontrib><creatorcontrib>Garrett, E M</creatorcontrib><creatorcontrib>Wafford, K A</creatorcontrib><creatorcontrib>Bain, C</creatorcontrib><creatorcontrib>Heavens, R P</creatorcontrib><creatorcontrib>Sirinathsinghji, D J</creatorcontrib><creatorcontrib>Whiting, P J</creatorcontrib><title>Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>A cDNA encoding the human gamma-aminobutyric acidA (GABAA) receptor alpha 6 subunit has been cloned and sequenced. The deduced
amino acid sequence of this cDNA shows 91.4% identity with the published rat alpha 6 subunit. In situ hybridization histochemistry
reveals the alpha 6 mRNA to be located within the granule cell layer of the human cerebellar cortex. Recombinant human alpha
6 beta gamma 2S GABAA receptors have been expressed in both stably transfected cells and Xenopus oocytes, and the pharmacology
of the benzodiazepine binding site has been determined. The recombinant receptor has a diazepam-insensitive pharmacology,
with negligible affinity for a number of classic benzodiazepines. A number of compounds that bind to the benzodiazepine site
potentiated the GABA response of alpha 6 beta 2 gamma 2 receptors. Most importantly, the classic benzodiazepine antagonist
ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788) and the partial
inverse agonist ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-4513)
both acted as agonists at the alpha 6 containing receptor. This observation demonstrates definitively that efficacy of benzodiazepine
compounds cannot be generalized across receptor subtypes and may also help explain some of the behavioral effects that have
been reported for these compounds.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antisense Elements (Genetics)</subject><subject>Autoradiography</subject><subject>Base Sequence</subject><subject>Cerebellar Cortex - metabolism</subject><subject>Cloning, Molecular</subject><subject>DNA Primers</subject><subject>DNA, Complementary</subject><subject>Female</subject><subject>Flunitrazepam - pharmacology</subject><subject>gamma-Aminobutyric Acid - pharmacology</subject><subject>Humans</subject><subject>In Situ Hybridization</subject><subject>Kinetics</subject><subject>L Cells (Cell Line)</subject><subject>Ligands</subject><subject>Macromolecular Substances</subject><subject>Membrane Potentials - drug effects</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Oocytes - drug effects</subject><subject>Oocytes - physiology</subject><subject>Pentobarbital - pharmacology</subject><subject>Polymerase Chain Reaction</subject><subject>Pregnanolone - pharmacology</subject><subject>Rats</subject><subject>Receptors, GABA-A - biosynthesis</subject><subject>Receptors, GABA-A - chemistry</subject><subject>Receptors, GABA-A - physiology</subject><subject>Recombinant Proteins - biosynthesis</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - metabolism</subject><subject>RNA, Messenger - analysis</subject><subject>RNA, Messenger - biosynthesis</subject><subject>Sequence Homology, Amino Acid</subject><subject>Transfection</subject><subject>Xenopus</subject><subject>Xenopus laevis</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtLxDAUhYsoOj5-gpCN7gppmke7HMYnDLpRcFfuJHemkTapSYqMv8cf6oyO4M7VhXO-e-7l7GWTQrAip0VR7GcTSpnMq1q8HGXHMb5SWnBR0cPssJIlU0JNss9Z5511K-KXRF89TCNBp73ZKqlF0o49OLKCvocceuv8YkzrYDUBbQ1J6wHJlATUOCQfCHRDC0SSOC5GZxMBZ4huIYBOGOwHJOvd9tA2eUOGHrTv_Gq91Xa7ufYugf1-6Tc3nmYHS-ginu3mSfZ8c_00u8vnj7f3s-k8b4u6TrkygILXimspDKKUtWKl0moTQzmv6yVU1RKNREUlZ5xJI4SR3HBe0dJQVp5klz-5Q_BvI8bU9DZq7Dpw6MfYqIqKUin1L1goKiom6QY834HjokfTDMH2ENbNrv-Nf_Hjt3bVvtuAzd9eGl43rGGiLL8ASMSRzw</recordid><startdate>19960201</startdate><enddate>19960201</enddate><creator>Hadingham, K L</creator><creator>Garrett, E M</creator><creator>Wafford, K A</creator><creator>Bain, C</creator><creator>Heavens, R P</creator><creator>Sirinathsinghji, D J</creator><creator>Whiting, P J</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>19960201</creationdate><title>Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors</title><author>Hadingham, K L ; Garrett, E M ; Wafford, K A ; Bain, C ; Heavens, R P ; Sirinathsinghji, D J ; Whiting, P J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h199t-7dae54974c65dee6697237c7ece04499fa88fed6e70642426d55d64d44803d023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Antisense Elements (Genetics)</topic><topic>Autoradiography</topic><topic>Base Sequence</topic><topic>Cerebellar Cortex - metabolism</topic><topic>Cloning, Molecular</topic><topic>DNA Primers</topic><topic>DNA, Complementary</topic><topic>Female</topic><topic>Flunitrazepam - pharmacology</topic><topic>gamma-Aminobutyric Acid - pharmacology</topic><topic>Humans</topic><topic>In Situ Hybridization</topic><topic>Kinetics</topic><topic>L Cells (Cell Line)</topic><topic>Ligands</topic><topic>Macromolecular Substances</topic><topic>Membrane Potentials - drug effects</topic><topic>Mice</topic><topic>Molecular Sequence Data</topic><topic>Oocytes - drug effects</topic><topic>Oocytes - physiology</topic><topic>Pentobarbital - pharmacology</topic><topic>Polymerase Chain Reaction</topic><topic>Pregnanolone - pharmacology</topic><topic>Rats</topic><topic>Receptors, GABA-A - biosynthesis</topic><topic>Receptors, GABA-A - chemistry</topic><topic>Receptors, GABA-A - physiology</topic><topic>Recombinant Proteins - biosynthesis</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - metabolism</topic><topic>RNA, Messenger - analysis</topic><topic>RNA, Messenger - biosynthesis</topic><topic>Sequence Homology, Amino Acid</topic><topic>Transfection</topic><topic>Xenopus</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hadingham, K L</creatorcontrib><creatorcontrib>Garrett, E M</creatorcontrib><creatorcontrib>Wafford, K A</creatorcontrib><creatorcontrib>Bain, C</creatorcontrib><creatorcontrib>Heavens, R P</creatorcontrib><creatorcontrib>Sirinathsinghji, D J</creatorcontrib><creatorcontrib>Whiting, P J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hadingham, K L</au><au>Garrett, E M</au><au>Wafford, K A</au><au>Bain, C</au><au>Heavens, R P</au><au>Sirinathsinghji, D J</au><au>Whiting, P J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1996-02-01</date><risdate>1996</risdate><volume>49</volume><issue>2</issue><spage>253</spage><epage>259</epage><pages>253-259</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>A cDNA encoding the human gamma-aminobutyric acidA (GABAA) receptor alpha 6 subunit has been cloned and sequenced. The deduced
amino acid sequence of this cDNA shows 91.4% identity with the published rat alpha 6 subunit. In situ hybridization histochemistry
reveals the alpha 6 mRNA to be located within the granule cell layer of the human cerebellar cortex. Recombinant human alpha
6 beta gamma 2S GABAA receptors have been expressed in both stably transfected cells and Xenopus oocytes, and the pharmacology
of the benzodiazepine binding site has been determined. The recombinant receptor has a diazepam-insensitive pharmacology,
with negligible affinity for a number of classic benzodiazepines. A number of compounds that bind to the benzodiazepine site
potentiated the GABA response of alpha 6 beta 2 gamma 2 receptors. Most importantly, the classic benzodiazepine antagonist
ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788) and the partial
inverse agonist ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-4513)
both acted as agonists at the alpha 6 containing receptor. This observation demonstrates definitively that efficacy of benzodiazepine
compounds cannot be generalized across receptor subtypes and may also help explain some of the behavioral effects that have
been reported for these compounds.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>8632757</pmid><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0026-895X |
| ispartof | Molecular pharmacology, 1996-02, Vol.49 (2), p.253-259 |
| issn | 0026-895X 1521-0111 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_78053777 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | Amino Acid Sequence Animals Antisense Elements (Genetics) Autoradiography Base Sequence Cerebellar Cortex - metabolism Cloning, Molecular DNA Primers DNA, Complementary Female Flunitrazepam - pharmacology gamma-Aminobutyric Acid - pharmacology Humans In Situ Hybridization Kinetics L Cells (Cell Line) Ligands Macromolecular Substances Membrane Potentials - drug effects Mice Molecular Sequence Data Oocytes - drug effects Oocytes - physiology Pentobarbital - pharmacology Polymerase Chain Reaction Pregnanolone - pharmacology Rats Receptors, GABA-A - biosynthesis Receptors, GABA-A - chemistry Receptors, GABA-A - physiology Recombinant Proteins - biosynthesis Recombinant Proteins - chemistry Recombinant Proteins - metabolism RNA, Messenger - analysis RNA, Messenger - biosynthesis Sequence Homology, Amino Acid Transfection Xenopus Xenopus laevis |
| title | Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors |
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