Methionine 286 in transmembrane domain 3 of the GABAA receptor β subunit controls a binding cavity for propofol and other alkylphenol general anesthetics
gamma-Aminobutyric acid type A (GABA(A)) receptors are an important target for general anesthetics in the central nervous system. Site-directed mutagenesis techniques have identified amino acid residues that are important for the positive modulation of GABA(A) receptors by general anesthetics. In th...
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| Veröffentlicht in: | Neuropharmacology 2001-12, Vol.41 (8), p.952-964 |
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| creator | KRASOWSKI, M. D NISHIKAWA, K NIKOLAEVA, N LIN, A HARRISON, N. L |
| description | gamma-Aminobutyric acid type A (GABA(A)) receptors are an important target for general anesthetics in the central nervous system. Site-directed mutagenesis techniques have identified amino acid residues that are important for the positive modulation of GABA(A) receptors by general anesthetics. In the present study, we investigate the role of an amino acid residue in transmembrane (TM) domain 3 of the GABA(A) receptor beta(2) subunit for modulation by the general anesthetic 2,6-diisopropylphenol (propofol). Mutation of methionine 286 to tryptophan (M286W) in the beta(2) subunit abolished potentiation of GABA responses by propofol but did not affect direct receptor activation by propofol in the absence of GABA. In contrast, substitution of methionine 286 by alanine, cysteine, glutamate, lysine, phenylalanine, serine, or tyrosine was permissive for potentiation of GABA responses and direct activation by propofol. Using propofol analogs of varying molecular size, we show that the beta(2)(M286W) mutation resulted in a decrease in the 'cut-off' volume for propofol analog molecules to enhance GABA responses at GABA(A) alpha(1)beta(2)gamma(2s) receptors. This suggests that mutation of M286 in the GABA(A) beta(2) subunit alters the dimensions of a 'binding pocket' for propofol and related alkylphenol general anesthetics. |
| doi_str_mv | 10.1016/S0028-3908(01)00141-1 |
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D ; NISHIKAWA, K ; NIKOLAEVA, N ; LIN, A ; HARRISON, N. L</creator><creatorcontrib>KRASOWSKI, M. D ; NISHIKAWA, K ; NIKOLAEVA, N ; LIN, A ; HARRISON, N. L</creatorcontrib><description>gamma-Aminobutyric acid type A (GABA(A)) receptors are an important target for general anesthetics in the central nervous system. Site-directed mutagenesis techniques have identified amino acid residues that are important for the positive modulation of GABA(A) receptors by general anesthetics. In the present study, we investigate the role of an amino acid residue in transmembrane (TM) domain 3 of the GABA(A) receptor beta(2) subunit for modulation by the general anesthetic 2,6-diisopropylphenol (propofol). Mutation of methionine 286 to tryptophan (M286W) in the beta(2) subunit abolished potentiation of GABA responses by propofol but did not affect direct receptor activation by propofol in the absence of GABA. In contrast, substitution of methionine 286 by alanine, cysteine, glutamate, lysine, phenylalanine, serine, or tyrosine was permissive for potentiation of GABA responses and direct activation by propofol. Using propofol analogs of varying molecular size, we show that the beta(2)(M286W) mutation resulted in a decrease in the 'cut-off' volume for propofol analog molecules to enhance GABA responses at GABA(A) alpha(1)beta(2)gamma(2s) receptors. This suggests that mutation of M286 in the GABA(A) beta(2) subunit alters the dimensions of a 'binding pocket' for propofol and related alkylphenol general anesthetics.</description><identifier>ISSN: 0028-3908</identifier><identifier>EISSN: 1873-7064</identifier><identifier>DOI: 10.1016/S0028-3908(01)00141-1</identifier><identifier>PMID: 11747900</identifier><identifier>CODEN: NEPHBW</identifier><language>eng</language><publisher>Oxford: Elsevier</publisher><subject>Amino Acid Sequence ; Amino Acid Substitution - genetics ; Aminoacid receptors (glycine, glutamate, gaba) ; Anesthetics, General - chemistry ; Anesthetics, General - metabolism ; Anesthetics, Intravenous - chemistry ; Anesthetics, Intravenous - metabolism ; Anesthetics. Neuromuscular blocking agents ; Animals ; Binding Sites - drug effects ; Binding Sites - genetics ; Biological and medical sciences ; Cell Line ; Cell receptors ; Cell structures and functions ; Dose-Response Relationship, Drug ; Etomidate - pharmacology ; Fundamental and applied biological sciences. Psychology ; gamma-Aminobutyric Acid - pharmacology ; Humans ; Medical sciences ; Methionine - genetics ; Methionine - pharmacology ; Methohexital - pharmacology ; Molecular and cellular biology ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Mutation ; Neuropharmacology ; Pharmacology. Drug treatments ; Propofol - chemistry ; Propofol - metabolism ; Protein Structure, Tertiary - genetics ; Rats ; Receptors, GABA-A - genetics ; Receptors, GABA-A - physiology</subject><ispartof>Neuropharmacology, 2001-12, Vol.41 (8), p.952-964</ispartof><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4041-717cf8a37cf6814bdd6e0b74dc13be162b3911cb1a3e9af8c2a71de6015da0b93</citedby><cites>FETCH-LOGICAL-c4041-717cf8a37cf6814bdd6e0b74dc13be162b3911cb1a3e9af8c2a71de6015da0b93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13414347$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11747900$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KRASOWSKI, M. D</creatorcontrib><creatorcontrib>NISHIKAWA, K</creatorcontrib><creatorcontrib>NIKOLAEVA, N</creatorcontrib><creatorcontrib>LIN, A</creatorcontrib><creatorcontrib>HARRISON, N. L</creatorcontrib><title>Methionine 286 in transmembrane domain 3 of the GABAA receptor β subunit controls a binding cavity for propofol and other alkylphenol general anesthetics</title><title>Neuropharmacology</title><addtitle>Neuropharmacology</addtitle><description>gamma-Aminobutyric acid type A (GABA(A)) receptors are an important target for general anesthetics in the central nervous system. Site-directed mutagenesis techniques have identified amino acid residues that are important for the positive modulation of GABA(A) receptors by general anesthetics. In the present study, we investigate the role of an amino acid residue in transmembrane (TM) domain 3 of the GABA(A) receptor beta(2) subunit for modulation by the general anesthetic 2,6-diisopropylphenol (propofol). Mutation of methionine 286 to tryptophan (M286W) in the beta(2) subunit abolished potentiation of GABA responses by propofol but did not affect direct receptor activation by propofol in the absence of GABA. In contrast, substitution of methionine 286 by alanine, cysteine, glutamate, lysine, phenylalanine, serine, or tyrosine was permissive for potentiation of GABA responses and direct activation by propofol. Using propofol analogs of varying molecular size, we show that the beta(2)(M286W) mutation resulted in a decrease in the 'cut-off' volume for propofol analog molecules to enhance GABA responses at GABA(A) alpha(1)beta(2)gamma(2s) receptors. This suggests that mutation of M286 in the GABA(A) beta(2) subunit alters the dimensions of a 'binding pocket' for propofol and related alkylphenol general anesthetics.</description><subject>Amino Acid Sequence</subject><subject>Amino Acid Substitution - genetics</subject><subject>Aminoacid receptors (glycine, glutamate, gaba)</subject><subject>Anesthetics, General - chemistry</subject><subject>Anesthetics, General - metabolism</subject><subject>Anesthetics, Intravenous - chemistry</subject><subject>Anesthetics, Intravenous - metabolism</subject><subject>Anesthetics. Neuromuscular blocking agents</subject><subject>Animals</subject><subject>Binding Sites - drug effects</subject><subject>Binding Sites - genetics</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cell receptors</subject><subject>Cell structures and functions</subject><subject>Dose-Response Relationship, Drug</subject><subject>Etomidate - pharmacology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>gamma-Aminobutyric Acid - pharmacology</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Methionine - genetics</subject><subject>Methionine - pharmacology</subject><subject>Methohexital - pharmacology</subject><subject>Molecular and cellular biology</subject><subject>Molecular Sequence Data</subject><subject>Mutagenesis, Site-Directed</subject><subject>Mutation</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Propofol - chemistry</subject><subject>Propofol - metabolism</subject><subject>Protein Structure, Tertiary - genetics</subject><subject>Rats</subject><subject>Receptors, GABA-A - genetics</subject><subject>Receptors, GABA-A - physiology</subject><issn>0028-3908</issn><issn>1873-7064</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1u1DAQxy0EotvCI4B8QYJDYCb2Jt4L0raCglTEAThbtjPZNSR2ZGcr7avwGDwIz1Rvu2rh4pHm_2GNfoy9QHiLgM27bwC1qsQK1GvANwAoscJHbIGqFVULjXzMFveWE3aa808AkArVU3aC2Mp2BbBgv7_QvPUx-EC8Vg33gc_JhDzSaMsk3sXRlKXgsefzlvjl-ny95okcTXNM_O8fnnd2F_zMXQxzikPmhlsfOh823JlrP-95X4xTilPs48BN6HgsTYmb4dd-mLYUynZDgZI5qJSLOHuXn7EnvRkyPT_OM_bj44fvF5-qq6-Xny_WV5WTUI5usXW9MqK8jUJpu64hsK3sHApL2NRWrBCdRSNoZXrlatNiRw3gsjNgV-KMvb_rnXZ2pM5ROcMMekp-NGmvo_H6fyX4rd7Ea12r5bLGphQs7wpcijkn6u-zCPoAS9_C0gcSGlDfwtJYci___fghdaRTDK-OBpOdGfoCxPn84BMSpZCtuAGvb6Gb</recordid><startdate>20011201</startdate><enddate>20011201</enddate><creator>KRASOWSKI, M. 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L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4041-717cf8a37cf6814bdd6e0b74dc13be162b3911cb1a3e9af8c2a71de6015da0b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Amino Acid Sequence</topic><topic>Amino Acid Substitution - genetics</topic><topic>Aminoacid receptors (glycine, glutamate, gaba)</topic><topic>Anesthetics, General - chemistry</topic><topic>Anesthetics, General - metabolism</topic><topic>Anesthetics, Intravenous - chemistry</topic><topic>Anesthetics, Intravenous - metabolism</topic><topic>Anesthetics. Neuromuscular blocking agents</topic><topic>Animals</topic><topic>Binding Sites - drug effects</topic><topic>Binding Sites - genetics</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Cell receptors</topic><topic>Cell structures and functions</topic><topic>Dose-Response Relationship, Drug</topic><topic>Etomidate - pharmacology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>gamma-Aminobutyric Acid - pharmacology</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Methionine - genetics</topic><topic>Methionine - pharmacology</topic><topic>Methohexital - pharmacology</topic><topic>Molecular and cellular biology</topic><topic>Molecular Sequence Data</topic><topic>Mutagenesis, Site-Directed</topic><topic>Mutation</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Propofol - chemistry</topic><topic>Propofol - metabolism</topic><topic>Protein Structure, Tertiary - genetics</topic><topic>Rats</topic><topic>Receptors, GABA-A - genetics</topic><topic>Receptors, GABA-A - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KRASOWSKI, M. D</creatorcontrib><creatorcontrib>NISHIKAWA, K</creatorcontrib><creatorcontrib>NIKOLAEVA, N</creatorcontrib><creatorcontrib>LIN, A</creatorcontrib><creatorcontrib>HARRISON, N. 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L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methionine 286 in transmembrane domain 3 of the GABAA receptor β subunit controls a binding cavity for propofol and other alkylphenol general anesthetics</atitle><jtitle>Neuropharmacology</jtitle><addtitle>Neuropharmacology</addtitle><date>2001-12-01</date><risdate>2001</risdate><volume>41</volume><issue>8</issue><spage>952</spage><epage>964</epage><pages>952-964</pages><issn>0028-3908</issn><eissn>1873-7064</eissn><coden>NEPHBW</coden><abstract>gamma-Aminobutyric acid type A (GABA(A)) receptors are an important target for general anesthetics in the central nervous system. Site-directed mutagenesis techniques have identified amino acid residues that are important for the positive modulation of GABA(A) receptors by general anesthetics. In the present study, we investigate the role of an amino acid residue in transmembrane (TM) domain 3 of the GABA(A) receptor beta(2) subunit for modulation by the general anesthetic 2,6-diisopropylphenol (propofol). Mutation of methionine 286 to tryptophan (M286W) in the beta(2) subunit abolished potentiation of GABA responses by propofol but did not affect direct receptor activation by propofol in the absence of GABA. In contrast, substitution of methionine 286 by alanine, cysteine, glutamate, lysine, phenylalanine, serine, or tyrosine was permissive for potentiation of GABA responses and direct activation by propofol. Using propofol analogs of varying molecular size, we show that the beta(2)(M286W) mutation resulted in a decrease in the 'cut-off' volume for propofol analog molecules to enhance GABA responses at GABA(A) alpha(1)beta(2)gamma(2s) receptors. This suggests that mutation of M286 in the GABA(A) beta(2) subunit alters the dimensions of a 'binding pocket' for propofol and related alkylphenol general anesthetics.</abstract><cop>Oxford</cop><pub>Elsevier</pub><pmid>11747900</pmid><doi>10.1016/S0028-3908(01)00141-1</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Amino Acid Substitution - genetics Aminoacid receptors (glycine, glutamate, gaba) Anesthetics, General - chemistry Anesthetics, General - metabolism Anesthetics, Intravenous - chemistry Anesthetics, Intravenous - metabolism Anesthetics. Neuromuscular blocking agents Animals Binding Sites - drug effects Binding Sites - genetics Biological and medical sciences Cell Line Cell receptors Cell structures and functions Dose-Response Relationship, Drug Etomidate - pharmacology Fundamental and applied biological sciences. Psychology gamma-Aminobutyric Acid - pharmacology Humans Medical sciences Methionine - genetics Methionine - pharmacology Methohexital - pharmacology Molecular and cellular biology Molecular Sequence Data Mutagenesis, Site-Directed Mutation Neuropharmacology Pharmacology. Drug treatments Propofol - chemistry Propofol - metabolism Protein Structure, Tertiary - genetics Rats Receptors, GABA-A - genetics Receptors, GABA-A - physiology |
| title | Methionine 286 in transmembrane domain 3 of the GABAA receptor β subunit controls a binding cavity for propofol and other alkylphenol general anesthetics |
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