Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator γ‐hydroxybutyrate
ABSTRACT γ‐Hydroxybutyrate (GHB) is an endogenous neuromodulator with therapeutical applications in anesthesia, sleep disorders, and drug addiction. We report the cloning of a GHB receptor from a rat hippocampal cDNA library. This receptor has a molecular mass of 56 kDa and belongs to the seven‐tran...
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| Veröffentlicht in: | The FASEB journal 2003-09, Vol.17 (12), p.1691-1693 |
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| creator | Andriamampandry, Christian Taleb, Omar Viry, Sandrine Muller, Claude Humbert, Jean Paul Gobaille, Serge Aunis, Dominique Maitre, Michel |
| description | ABSTRACT
γ‐Hydroxybutyrate (GHB) is an endogenous neuromodulator with therapeutical applications in anesthesia, sleep disorders, and drug addiction. We report the cloning of a GHB receptor from a rat hippocampal cDNA library. This receptor has a molecular mass of 56 kDa and belongs to the seven‐transmembrane receptor family. The peptidic sequence has no significant homology with any known receptor, including GABAB receptors. Its mRNA is restricted to the brain and is particularly abundant in the hippocampus, cortex, striatum, thalamus, olfactory bulbs, and cerebellum, matching the distribution of GHB binding sites in rat brain. Southern blot revealed the presence of homologous sequences in several species including the human. Binding assays on transfected CHO cells showed a dissociation constant (Kd) of 426 nM for GHB and no affinity for GABA, baclofen, or glutamate. In patch‐clamp experiments, transfected CHO cells revealed a functional G‐protein‐coupled receptor as demonstrated by GTP‐γ‐S‐induced irreversible activation. Application of 0.1‐15 µM GHB specifically induced an inward current at negative membrane potentials that was not reproduced by application of baclofen (10 µM). CGP‐55845, a GABAB receptor antagonist, did not inhibit the GHB‐induced response nor did the GHB receptor antagonist NCS‐382, suggesting that the GHB receptor system includes several subtypes. |
| doi_str_mv | 10.1096/fj.02-0846fje |
| format | Article |
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γ‐Hydroxybutyrate (GHB) is an endogenous neuromodulator with therapeutical applications in anesthesia, sleep disorders, and drug addiction. We report the cloning of a GHB receptor from a rat hippocampal cDNA library. This receptor has a molecular mass of 56 kDa and belongs to the seven‐transmembrane receptor family. The peptidic sequence has no significant homology with any known receptor, including GABAB receptors. Its mRNA is restricted to the brain and is particularly abundant in the hippocampus, cortex, striatum, thalamus, olfactory bulbs, and cerebellum, matching the distribution of GHB binding sites in rat brain. Southern blot revealed the presence of homologous sequences in several species including the human. Binding assays on transfected CHO cells showed a dissociation constant (Kd) of 426 nM for GHB and no affinity for GABA, baclofen, or glutamate. In patch‐clamp experiments, transfected CHO cells revealed a functional G‐protein‐coupled receptor as demonstrated by GTP‐γ‐S‐induced irreversible activation. Application of 0.1‐15 µM GHB specifically induced an inward current at negative membrane potentials that was not reproduced by application of baclofen (10 µM). CGP‐55845, a GABAB receptor antagonist, did not inhibit the GHB‐induced response nor did the GHB receptor antagonist NCS‐382, suggesting that the GHB receptor system includes several subtypes.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.02-0846fje</identifier><identifier>PMID: 12958178</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Brain Chemistry ; CHO Cells ; Cloning, Molecular ; Cricetinae ; drug of abuse ; GHB ; Humans ; Patch-Clamp Techniques ; Protein Structure, Secondary ; Rats ; receptor for neuromodulator ; Receptors, Cell Surface - chemistry ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - metabolism ; RNA, Messenger - analysis ; Sequence Homology, Amino Acid ; sleep regulation ; Sodium Oxybate - metabolism ; Transfection</subject><ispartof>The FASEB journal, 2003-09, Vol.17 (12), p.1691-1693</ispartof><rights>FASEB</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c371E-c3c118082a4f55980fd749c962ae93ee5f80cd3389d5ffabc2e7d55793eba24c3</citedby><cites>FETCH-LOGICAL-c371E-c3c118082a4f55980fd749c962ae93ee5f80cd3389d5ffabc2e7d55793eba24c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.02-0846fje$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.02-0846fje$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,778,782,1414,27907,27908,45557,45558</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12958178$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Andriamampandry, Christian</creatorcontrib><creatorcontrib>Taleb, Omar</creatorcontrib><creatorcontrib>Viry, Sandrine</creatorcontrib><creatorcontrib>Muller, Claude</creatorcontrib><creatorcontrib>Humbert, Jean Paul</creatorcontrib><creatorcontrib>Gobaille, Serge</creatorcontrib><creatorcontrib>Aunis, Dominique</creatorcontrib><creatorcontrib>Maitre, Michel</creatorcontrib><title>Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator γ‐hydroxybutyrate</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>ABSTRACT
γ‐Hydroxybutyrate (GHB) is an endogenous neuromodulator with therapeutical applications in anesthesia, sleep disorders, and drug addiction. We report the cloning of a GHB receptor from a rat hippocampal cDNA library. This receptor has a molecular mass of 56 kDa and belongs to the seven‐transmembrane receptor family. The peptidic sequence has no significant homology with any known receptor, including GABAB receptors. Its mRNA is restricted to the brain and is particularly abundant in the hippocampus, cortex, striatum, thalamus, olfactory bulbs, and cerebellum, matching the distribution of GHB binding sites in rat brain. Southern blot revealed the presence of homologous sequences in several species including the human. Binding assays on transfected CHO cells showed a dissociation constant (Kd) of 426 nM for GHB and no affinity for GABA, baclofen, or glutamate. In patch‐clamp experiments, transfected CHO cells revealed a functional G‐protein‐coupled receptor as demonstrated by GTP‐γ‐S‐induced irreversible activation. Application of 0.1‐15 µM GHB specifically induced an inward current at negative membrane potentials that was not reproduced by application of baclofen (10 µM). CGP‐55845, a GABAB receptor antagonist, did not inhibit the GHB‐induced response nor did the GHB receptor antagonist NCS‐382, suggesting that the GHB receptor system includes several subtypes.</description><subject>Animals</subject><subject>Brain Chemistry</subject><subject>CHO Cells</subject><subject>Cloning, Molecular</subject><subject>Cricetinae</subject><subject>drug of abuse</subject><subject>GHB</subject><subject>Humans</subject><subject>Patch-Clamp Techniques</subject><subject>Protein Structure, Secondary</subject><subject>Rats</subject><subject>receptor for neuromodulator</subject><subject>Receptors, Cell Surface - chemistry</subject><subject>Receptors, Cell Surface - genetics</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>RNA, Messenger - analysis</subject><subject>Sequence Homology, Amino Acid</subject><subject>sleep regulation</subject><subject>Sodium Oxybate - metabolism</subject><subject>Transfection</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkb2OEzEQxy0E4sJBSYtc0e0xtrNeLx1EycHpJAqgtrz2-LLRxg72rmCpeATe5d6Dh-BJcJRIdNDM50__Gc0Q8pzBFYNWvvK7K-AVqKX0O3xAFqwWUEkl4SFZgGp5JaVQF-RJzjsAYMDkY3LBeFsr1qgFSashhj7cURMctVuTjB0x9d_N2MdAo6eGJjPSLpk-0IQWD2NMdNwea31wuYRIMbh4hyFOmQacUtxHNw3mCP66__3j53Z2KX6bu2mcixY-JY-8GTI-O_tL8nmz_rR6V91-uH6_enNbWdGwdbGWMQWKm6Wv61aBd82yta3kBluBWHsF1gmhWld7bzrLsXF13ZReZ_jSikvy8qR7SPHLhHnU-z5bHAYTsKyqGyGZko36L8gaJngZVMDqBNoUc07o9SH1e5NmzUAfv6H9TgPX528U_sVZeOr26P7S5_MX4PUJ-NoPOP9bTW8-vuWbG-DHfHOzFn8AP1Ocug</recordid><startdate>200309</startdate><enddate>200309</enddate><creator>Andriamampandry, Christian</creator><creator>Taleb, Omar</creator><creator>Viry, Sandrine</creator><creator>Muller, Claude</creator><creator>Humbert, Jean Paul</creator><creator>Gobaille, Serge</creator><creator>Aunis, Dominique</creator><creator>Maitre, Michel</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>7X8</scope></search><sort><creationdate>200309</creationdate><title>Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator γ‐hydroxybutyrate</title><author>Andriamampandry, Christian ; 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γ‐Hydroxybutyrate (GHB) is an endogenous neuromodulator with therapeutical applications in anesthesia, sleep disorders, and drug addiction. We report the cloning of a GHB receptor from a rat hippocampal cDNA library. This receptor has a molecular mass of 56 kDa and belongs to the seven‐transmembrane receptor family. The peptidic sequence has no significant homology with any known receptor, including GABAB receptors. Its mRNA is restricted to the brain and is particularly abundant in the hippocampus, cortex, striatum, thalamus, olfactory bulbs, and cerebellum, matching the distribution of GHB binding sites in rat brain. Southern blot revealed the presence of homologous sequences in several species including the human. Binding assays on transfected CHO cells showed a dissociation constant (Kd) of 426 nM for GHB and no affinity for GABA, baclofen, or glutamate. In patch‐clamp experiments, transfected CHO cells revealed a functional G‐protein‐coupled receptor as demonstrated by GTP‐γ‐S‐induced irreversible activation. Application of 0.1‐15 µM GHB specifically induced an inward current at negative membrane potentials that was not reproduced by application of baclofen (10 µM). CGP‐55845, a GABAB receptor antagonist, did not inhibit the GHB‐induced response nor did the GHB receptor antagonist NCS‐382, suggesting that the GHB receptor system includes several subtypes.</abstract><cop>United States</cop><pmid>12958178</pmid><doi>10.1096/fj.02-0846fje</doi><tpages>29</tpages></addata></record> |
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| subjects | Animals Brain Chemistry CHO Cells Cloning, Molecular Cricetinae drug of abuse GHB Humans Patch-Clamp Techniques Protein Structure, Secondary Rats receptor for neuromodulator Receptors, Cell Surface - chemistry Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism RNA, Messenger - analysis Sequence Homology, Amino Acid sleep regulation Sodium Oxybate - metabolism Transfection |
| title | Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator γ‐hydroxybutyrate |
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