Modulation of Ionotropic GABA Receptors by 6-Methoxyflavanone and 6-Methoxyflavone
We evaluated the effects of 6-methoxyflavanone and 6-methoxyflavone on wild-type α1/α2β2γ2L GABA A and ρ1 GABA C receptors and on mutant ρ1I307S, ρ1W328 M, ρ1I307S/W328 M GABA C receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6...
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| Veröffentlicht in: | Neurochemical research 2014-06, Vol.39 (6), p.1068-1078 |
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| creator | Hall, Belinda J. Karim, Nasiara Chebib, Mary Johnston, Graham A. R. Hanrahan, Jane R. |
| description | We evaluated the effects of 6-methoxyflavanone and 6-methoxyflavone on wild-type α1/α2β2γ2L GABA
A
and ρ1 GABA
C
receptors and on mutant ρ1I307S, ρ1W328 M, ρ1I307S/W328 M GABA
C
receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant α1β2γ2L and α2β2γ2L GABA
A
receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at α1β2 GABA
A
receptors. 6-Methoxyflavanone inhibited [
3
H]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S and ρ1W328 M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive ρ1I307S/W328 M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328 M GABA receptors. The relative inactivity of 6-methoxyflavanone at α1β2 GABA
A
receptors and it’s partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids. |
| doi_str_mv | 10.1007/s11064-013-1157-2 |
| format | Article |
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A
and ρ1 GABA
C
receptors and on mutant ρ1I307S, ρ1W328 M, ρ1I307S/W328 M GABA
C
receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant α1β2γ2L and α2β2γ2L GABA
A
receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at α1β2 GABA
A
receptors. 6-Methoxyflavanone inhibited [
3
H]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S and ρ1W328 M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive ρ1I307S/W328 M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328 M GABA receptors. The relative inactivity of 6-methoxyflavanone at α1β2 GABA
A
receptors and it’s partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.</description><identifier>ISSN: 0364-3190</identifier><identifier>EISSN: 1573-6903</identifier><identifier>DOI: 10.1007/s11064-013-1157-2</identifier><identifier>PMID: 24078264</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Allosteric Regulation ; Animals ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cell Biology ; Flavanones - pharmacology ; Flavones - pharmacology ; Neurochemistry ; Neurology ; Neurosciences ; Original Paper ; Receptors, GABA - drug effects ; Receptors, GABA - metabolism ; Recombinant Proteins - drug effects ; Recombinant Proteins - metabolism ; Xenopus laevis</subject><ispartof>Neurochemical research, 2014-06, Vol.39 (6), p.1068-1078</ispartof><rights>Springer Science+Business Media New York 2013</rights><rights>Springer Science+Business Media New York 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-bc16e6d6da240b0e50268001255e079a4fbd24552bad46a809b8aa440b579a2d3</citedby><cites>FETCH-LOGICAL-c405t-bc16e6d6da240b0e50268001255e079a4fbd24552bad46a809b8aa440b579a2d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11064-013-1157-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11064-013-1157-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24078264$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hall, Belinda J.</creatorcontrib><creatorcontrib>Karim, Nasiara</creatorcontrib><creatorcontrib>Chebib, Mary</creatorcontrib><creatorcontrib>Johnston, Graham A. R.</creatorcontrib><creatorcontrib>Hanrahan, Jane R.</creatorcontrib><title>Modulation of Ionotropic GABA Receptors by 6-Methoxyflavanone and 6-Methoxyflavone</title><title>Neurochemical research</title><addtitle>Neurochem Res</addtitle><addtitle>Neurochem Res</addtitle><description>We evaluated the effects of 6-methoxyflavanone and 6-methoxyflavone on wild-type α1/α2β2γ2L GABA
A
and ρ1 GABA
C
receptors and on mutant ρ1I307S, ρ1W328 M, ρ1I307S/W328 M GABA
C
receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant α1β2γ2L and α2β2γ2L GABA
A
receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at α1β2 GABA
A
receptors. 6-Methoxyflavanone inhibited [
3
H]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S and ρ1W328 M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive ρ1I307S/W328 M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328 M GABA receptors. The relative inactivity of 6-methoxyflavanone at α1β2 GABA
A
receptors and it’s partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.</description><subject>Allosteric Regulation</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell Biology</subject><subject>Flavanones - pharmacology</subject><subject>Flavones - pharmacology</subject><subject>Neurochemistry</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Original Paper</subject><subject>Receptors, GABA - drug effects</subject><subject>Receptors, GABA - metabolism</subject><subject>Recombinant Proteins - drug effects</subject><subject>Recombinant Proteins - metabolism</subject><subject>Xenopus laevis</subject><issn>0364-3190</issn><issn>1573-6903</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkV9LwzAUxYMobk4_gC9S8MWX6M3fto9z6BxMhKHPIW1T7eiambTivr0ZnaKC-HThnt85ueEgdErgkgDEV54QkBwDYZgQEWO6h4ZhMixTYPtoCCyojKQwQEfeLwGCi5JDNKAc4oRKPkSLe1t0tW4r20S2jGa2sa2z6yqPpuPrcbQwuVm31vko20QS35v2xb5vylq_6cY2JtJN8XMdlsfooNS1Nye7OUJPtzePkzs8f5jOJuM5zjmIFmc5kUYWstDhmgyMACqTcCIVwkCcal5mBeVC0EwXXOoE0izRmgdWBJUWbIQu-ty1s6-d8a1aVT43da0bYzuviCQJ4ZBy_j8qGE-YECwO6PkvdGk714SPBIpyRhOSsECRnsqd9d6ZUq1dtdJuowiobTeq70aFbtS2G0WD52yX3GUrU3w5PssIAO0BH6Tm2bhvT_-Z-gFhsZbw</recordid><startdate>20140601</startdate><enddate>20140601</enddate><creator>Hall, Belinda J.</creator><creator>Karim, Nasiara</creator><creator>Chebib, Mary</creator><creator>Johnston, Graham A. 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R. ; Hanrahan, Jane R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-bc16e6d6da240b0e50268001255e079a4fbd24552bad46a809b8aa440b579a2d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Allosteric Regulation</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cell Biology</topic><topic>Flavanones - pharmacology</topic><topic>Flavones - pharmacology</topic><topic>Neurochemistry</topic><topic>Neurology</topic><topic>Neurosciences</topic><topic>Original Paper</topic><topic>Receptors, GABA - drug effects</topic><topic>Receptors, GABA - metabolism</topic><topic>Recombinant Proteins - drug effects</topic><topic>Recombinant Proteins - metabolism</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hall, Belinda J.</creatorcontrib><creatorcontrib>Karim, Nasiara</creatorcontrib><creatorcontrib>Chebib, Mary</creatorcontrib><creatorcontrib>Johnston, Graham A. R.</creatorcontrib><creatorcontrib>Hanrahan, Jane R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 1: Biological Sciences & Living Resources</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><collection>MEDLINE - Academic</collection><jtitle>Neurochemical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hall, Belinda J.</au><au>Karim, Nasiara</au><au>Chebib, Mary</au><au>Johnston, Graham A. R.</au><au>Hanrahan, Jane R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of Ionotropic GABA Receptors by 6-Methoxyflavanone and 6-Methoxyflavone</atitle><jtitle>Neurochemical research</jtitle><stitle>Neurochem Res</stitle><addtitle>Neurochem Res</addtitle><date>2014-06-01</date><risdate>2014</risdate><volume>39</volume><issue>6</issue><spage>1068</spage><epage>1078</epage><pages>1068-1078</pages><issn>0364-3190</issn><eissn>1573-6903</eissn><abstract>We evaluated the effects of 6-methoxyflavanone and 6-methoxyflavone on wild-type α1/α2β2γ2L GABA
A
and ρ1 GABA
C
receptors and on mutant ρ1I307S, ρ1W328 M, ρ1I307S/W328 M GABA
C
receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant α1β2γ2L and α2β2γ2L GABA
A
receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at α1β2 GABA
A
receptors. 6-Methoxyflavanone inhibited [
3
H]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S and ρ1W328 M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive ρ1I307S/W328 M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328 M GABA receptors. The relative inactivity of 6-methoxyflavanone at α1β2 GABA
A
receptors and it’s partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>24078264</pmid><doi>10.1007/s11064-013-1157-2</doi><tpages>11</tpages></addata></record> |
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| ispartof | Neurochemical research, 2014-06, Vol.39 (6), p.1068-1078 |
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| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Allosteric Regulation Animals Biochemistry Biomedical and Life Sciences Biomedicine Cell Biology Flavanones - pharmacology Flavones - pharmacology Neurochemistry Neurology Neurosciences Original Paper Receptors, GABA - drug effects Receptors, GABA - metabolism Recombinant Proteins - drug effects Recombinant Proteins - metabolism Xenopus laevis |
| title | Modulation of Ionotropic GABA Receptors by 6-Methoxyflavanone and 6-Methoxyflavone |
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