The β‐lactam antibiotics, penicillin‐G and cefoselis have different mechanisms and sites of action at GABAA receptors
The action of the β‐lactam antibiotics, penicillin‐G (PCG) and cefoselis (CFSL) on GABAA receptors (GABAA‐R) was investigated using the two‐electrode voltage clamp technique and Xenopus oocyte expressed murine GABAA‐R. Murine GABAA‐Rs were expressed in Xenopus oocytes by injecting cRNA that encoded...
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| Veröffentlicht in: | British journal of pharmacology 2002-01, Vol.135 (2), p.427-432 |
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| creator | Sugimoto, Masahiro Fukami, Sakae Kayakiri, Hiroshi Yamazaki, Shunji Matsuoka, Nobuya Uchida, Ichiro Mashimo, Takashi |
| description | The action of the β‐lactam antibiotics, penicillin‐G (PCG) and cefoselis (CFSL) on GABAA receptors (GABAA‐R) was investigated using the two‐electrode voltage clamp technique and Xenopus oocyte expressed murine GABAA‐R.
Murine GABAA‐Rs were expressed in Xenopus oocytes by injecting cRNA that encoded for each subunit (α1, β2, and γ2) and the effects of PCG and CFSL on the α1β2γ2s subunit receptors were examined using two‐electrode voltage clamp. Using the α1β2γ2s GABAA‐R, PCG and CFSL inhibited GABA‐induced currents in a concentration‐dependent manner, with IC50s of 557.1±125.4 and 185.0±26.6 μM, respectively. The inhibitory action of PCG on GABA‐induced currents was non‐competitive whereas that of CFSL was competitive.
Mutation of tyrosine to phenylalanine at position 256 in the β2 subunit (β2Y256F), which is reported to abolish the inhibitory effect of picrotoxin, drastically reduced the potency of PCG (IC50=28.4±1.42 mM) for the α1β2Y256Fγ2s receptor without changing the IC50 of CFSL (189±26.6 μM).
These electrophysiological data indicate that PCG and CFSL inhibit GABAA‐R in a different manner, with PCG acting non‐competitively and CFSL competitively. The mutational study indicates that PCG might act on an identical or nearby site to that of picrotoxin in the channel pore of the GABAA‐R.
British Journal of Pharmacology (2001) 135, 427–432; doi:10.1038/sj.bjp.0704496 |
| doi_str_mv | 10.1038/sj.bjp.0704496 |
| format | Article |
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Murine GABAA‐Rs were expressed in Xenopus oocytes by injecting cRNA that encoded for each subunit (α1, β2, and γ2) and the effects of PCG and CFSL on the α1β2γ2s subunit receptors were examined using two‐electrode voltage clamp. Using the α1β2γ2s GABAA‐R, PCG and CFSL inhibited GABA‐induced currents in a concentration‐dependent manner, with IC50s of 557.1±125.4 and 185.0±26.6 μM, respectively. The inhibitory action of PCG on GABA‐induced currents was non‐competitive whereas that of CFSL was competitive.
Mutation of tyrosine to phenylalanine at position 256 in the β2 subunit (β2Y256F), which is reported to abolish the inhibitory effect of picrotoxin, drastically reduced the potency of PCG (IC50=28.4±1.42 mM) for the α1β2Y256Fγ2s receptor without changing the IC50 of CFSL (189±26.6 μM).
These electrophysiological data indicate that PCG and CFSL inhibit GABAA‐R in a different manner, with PCG acting non‐competitively and CFSL competitively. The mutational study indicates that PCG might act on an identical or nearby site to that of picrotoxin in the channel pore of the GABAA‐R.
British Journal of Pharmacology (2001) 135, 427–432; doi:10.1038/sj.bjp.0704496</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0704496</identifier><identifier>PMID: 11815378</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Antibiotics ; Biological and medical sciences ; convulsion ; Drug toxicity and drugs side effects treatment ; electrophysiology ; GABAA receptor ; Medical sciences ; mutation ; Pharmacology. Drug treatments ; picrotoxin ; Toxicity: nervous system and muscle ; Xenopus oocytes</subject><ispartof>British journal of pharmacology, 2002-01, Vol.135 (2), p.427-432</ispartof><rights>2002 British Pharmacological Society</rights><rights>2002 INIST-CNRS</rights><rights>Copyright 2002, Nature Publishing Group 2002 Nature Publishing Group</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/PMC1573156/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1573156/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,1433,4024,27923,27924,27925,45574,45575,46409,46833,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13597087$$DView record in Pascal Francis$$Hfree_for_read</backlink></links><search><creatorcontrib>Sugimoto, Masahiro</creatorcontrib><creatorcontrib>Fukami, Sakae</creatorcontrib><creatorcontrib>Kayakiri, Hiroshi</creatorcontrib><creatorcontrib>Yamazaki, Shunji</creatorcontrib><creatorcontrib>Matsuoka, Nobuya</creatorcontrib><creatorcontrib>Uchida, Ichiro</creatorcontrib><creatorcontrib>Mashimo, Takashi</creatorcontrib><title>The β‐lactam antibiotics, penicillin‐G and cefoselis have different mechanisms and sites of action at GABAA receptors</title><title>British journal of pharmacology</title><description>The action of the β‐lactam antibiotics, penicillin‐G (PCG) and cefoselis (CFSL) on GABAA receptors (GABAA‐R) was investigated using the two‐electrode voltage clamp technique and Xenopus oocyte expressed murine GABAA‐R.
Murine GABAA‐Rs were expressed in Xenopus oocytes by injecting cRNA that encoded for each subunit (α1, β2, and γ2) and the effects of PCG and CFSL on the α1β2γ2s subunit receptors were examined using two‐electrode voltage clamp. Using the α1β2γ2s GABAA‐R, PCG and CFSL inhibited GABA‐induced currents in a concentration‐dependent manner, with IC50s of 557.1±125.4 and 185.0±26.6 μM, respectively. The inhibitory action of PCG on GABA‐induced currents was non‐competitive whereas that of CFSL was competitive.
Mutation of tyrosine to phenylalanine at position 256 in the β2 subunit (β2Y256F), which is reported to abolish the inhibitory effect of picrotoxin, drastically reduced the potency of PCG (IC50=28.4±1.42 mM) for the α1β2Y256Fγ2s receptor without changing the IC50 of CFSL (189±26.6 μM).
These electrophysiological data indicate that PCG and CFSL inhibit GABAA‐R in a different manner, with PCG acting non‐competitively and CFSL competitively. The mutational study indicates that PCG might act on an identical or nearby site to that of picrotoxin in the channel pore of the GABAA‐R.
British Journal of Pharmacology (2001) 135, 427–432; doi:10.1038/sj.bjp.0704496</description><subject>Antibiotics</subject><subject>Biological and medical sciences</subject><subject>convulsion</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>electrophysiology</subject><subject>GABAA receptor</subject><subject>Medical sciences</subject><subject>mutation</subject><subject>Pharmacology. Drug treatments</subject><subject>picrotoxin</subject><subject>Toxicity: nervous system and muscle</subject><subject>Xenopus oocytes</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNpVkc1OGzEURi1U1KRpt117w66TXo_teGZTKSBIkJBgAWvLY18TR_On8UCVrngEnoUH4SH6JJgSFbG6kr_jo3v1EfKdwZwBL37G7bza9nNQIES5OCBTJtQik7xgn8gUAFTGWFFMyJcYtwApVPIzmaQ3JrkqpuTP9Qbp89Pfh8fa2NE01LRjqEI3Bht_0B7bYENdhzYBq5Q5atF3EesQ6cbcI3XBexywHWmDdmPaEJv4j4thxEg7T5M2dC01I10tj5dLOqDFfuyG-JUcelNH_LafM3Jzdnp9ss4uLlfnJ8uLrM-5UpmpSqcElBzswjmXVx5EKZ0Dg69H59ZJaZB5K0rvATBHKKxgXkjJRK5yPiO_3rz9XdWgs2nZwdS6H0Jjhp3uTNAfkzZs9G13r5lUnMlFEhztBSZaU_vBtDbE_wLGZamgUInjb9zvUOPuPQf9WpWOW52q0vuq9PHVmpfp1wuUoY0y</recordid><startdate>200201</startdate><enddate>200201</enddate><creator>Sugimoto, Masahiro</creator><creator>Fukami, Sakae</creator><creator>Kayakiri, Hiroshi</creator><creator>Yamazaki, Shunji</creator><creator>Matsuoka, Nobuya</creator><creator>Uchida, Ichiro</creator><creator>Mashimo, Takashi</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing</general><scope>IQODW</scope><scope>5PM</scope></search><sort><creationdate>200201</creationdate><title>The β‐lactam antibiotics, penicillin‐G and cefoselis have different mechanisms and sites of action at GABAA receptors</title><author>Sugimoto, Masahiro ; Fukami, Sakae ; Kayakiri, Hiroshi ; Yamazaki, Shunji ; Matsuoka, Nobuya ; Uchida, Ichiro ; Mashimo, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p2377-ab9d740930c6ddd2bf0495dd0ae70442cd55ae1fc49ff00e2e08c41f455142723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Antibiotics</topic><topic>Biological and medical sciences</topic><topic>convulsion</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>electrophysiology</topic><topic>GABAA receptor</topic><topic>Medical sciences</topic><topic>mutation</topic><topic>Pharmacology. Drug treatments</topic><topic>picrotoxin</topic><topic>Toxicity: nervous system and muscle</topic><topic>Xenopus oocytes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sugimoto, Masahiro</creatorcontrib><creatorcontrib>Fukami, Sakae</creatorcontrib><creatorcontrib>Kayakiri, Hiroshi</creatorcontrib><creatorcontrib>Yamazaki, Shunji</creatorcontrib><creatorcontrib>Matsuoka, Nobuya</creatorcontrib><creatorcontrib>Uchida, Ichiro</creatorcontrib><creatorcontrib>Mashimo, Takashi</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>Sugimoto, Masahiro</au><au>Fukami, Sakae</au><au>Kayakiri, Hiroshi</au><au>Yamazaki, Shunji</au><au>Matsuoka, Nobuya</au><au>Uchida, Ichiro</au><au>Mashimo, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The β‐lactam antibiotics, penicillin‐G and cefoselis have different mechanisms and sites of action at GABAA receptors</atitle><jtitle>British journal of pharmacology</jtitle><date>2002-01</date><risdate>2002</risdate><volume>135</volume><issue>2</issue><spage>427</spage><epage>432</epage><pages>427-432</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>The action of the β‐lactam antibiotics, penicillin‐G (PCG) and cefoselis (CFSL) on GABAA receptors (GABAA‐R) was investigated using the two‐electrode voltage clamp technique and Xenopus oocyte expressed murine GABAA‐R.
Murine GABAA‐Rs were expressed in Xenopus oocytes by injecting cRNA that encoded for each subunit (α1, β2, and γ2) and the effects of PCG and CFSL on the α1β2γ2s subunit receptors were examined using two‐electrode voltage clamp. Using the α1β2γ2s GABAA‐R, PCG and CFSL inhibited GABA‐induced currents in a concentration‐dependent manner, with IC50s of 557.1±125.4 and 185.0±26.6 μM, respectively. The inhibitory action of PCG on GABA‐induced currents was non‐competitive whereas that of CFSL was competitive.
Mutation of tyrosine to phenylalanine at position 256 in the β2 subunit (β2Y256F), which is reported to abolish the inhibitory effect of picrotoxin, drastically reduced the potency of PCG (IC50=28.4±1.42 mM) for the α1β2Y256Fγ2s receptor without changing the IC50 of CFSL (189±26.6 μM).
These electrophysiological data indicate that PCG and CFSL inhibit GABAA‐R in a different manner, with PCG acting non‐competitively and CFSL competitively. The mutational study indicates that PCG might act on an identical or nearby site to that of picrotoxin in the channel pore of the GABAA‐R.
British Journal of Pharmacology (2001) 135, 427–432; doi:10.1038/sj.bjp.0704496</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>11815378</pmid><doi>10.1038/sj.bjp.0704496</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antibiotics Biological and medical sciences convulsion Drug toxicity and drugs side effects treatment electrophysiology GABAA receptor Medical sciences mutation Pharmacology. Drug treatments picrotoxin Toxicity: nervous system and muscle Xenopus oocytes |
| title | The β‐lactam antibiotics, penicillin‐G and cefoselis have different mechanisms and sites of action at GABAA receptors |
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