Subtypes of Sodium‐Dependent High‐Affinity L‐[3H]Glutamate Transport Activity: Pharmacologic Specificity and Regulation by Sodium and Potassium
: Some data suggest that the sodium‐dependent, high‐affinity L‐glutamate (Glu) transport sites in forebrain are different from those in cerebellum. In the present study, sodium‐dependent transport of L‐[3H]Glu was characterized in cerebellum and cortex. In both cerebellar and cortical tissue, activi...
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| Veröffentlicht in: | Journal of neurochemistry 1993-01, Vol.60 (1), p.167-179 |
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| creator | Robinson, Michael B. Sinor, Jeroo D. Dowd, Lisa A. Kerwin, James F. |
| description | : Some data suggest that the sodium‐dependent, high‐affinity L‐glutamate (Glu) transport sites in forebrain are different from those in cerebellum. In the present study, sodium‐dependent transport of L‐[3H]Glu was characterized in cerebellum and cortex. In both cerebellar and cortical tissue, activity was enriched in synaptosomes. Approximately 100 excitatory amino acid analogues were tested as potential inhibitors of transport activity. Many of the compounds tested inhibited transport activity by |
| doi_str_mv | 10.1111/j.1471-4159.1993.tb05835.x |
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In the present study, sodium‐dependent transport of L‐[3H]Glu was characterized in cerebellum and cortex. In both cerebellar and cortical tissue, activity was enriched in synaptosomes. Approximately 100 excitatory amino acid analogues were tested as potential inhibitors of transport activity. Many of the compounds tested inhibited transport activity by <65% at 1 mM and were not studied further. One group of compounds exhibited inhibition conforming to theoretical curves with Hill coefficients of 1 and were <10‐fold selective as inhibitors of transport activity. These included three of the putative endogenous substrates for transport: L‐Glu, L‐aspartate, and L‐cysteate. Four of the compounds exhibited inhibition conforming to theoretical curves with Hill coefficients of 1 and were > 10‐fold selective as inhibitors. These included β‐N‐oxalyl‐L‐α,β‐diaminopropionate, α‐methyl‐DL‐glutamate, (2S, 1′S,2′S)‐2‐(carboxycyclopropyl)glycine, and (2S, 1′S,2′S,3′S)‐2‐(2‐carboxy‐3‐methoxymethylcyclopropyl)glycine. Data obtained with a few of the inhibitors were consistent with two sites in one or both of the brain regions. (2S, 1′R,2′R)‐2‐(Carboxycyclopropyl)glycine (L‐CCG‐II) was identified as the most potent (IC50= 5.5 μM) and selective (60–100‐fold) inhibitor of transport activity in cerebellum. One of the potential endogenous substrates, L‐homocysteate, was also a selective inhibitor of cerebellar transport activity. The data for inhibition of transport activity in cortex by both L‐CCG‐II and L‐homocysteate were best fit to two sites. Kainate was equipotent as an inhibitor of transport activity, and in both brain regions the data for inhibition were best fit to two sites. The possibility that there are four subtypes of excitatory amino acid transport is discussed. Altering sodium and potassium levels affects cerebellar and cortical transport activity differently, suggesting that the differences extend to other recognition sites on these transporters.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1111/j.1471-4159.1993.tb05835.x</identifier><identifier>PMID: 8093259</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Analysis of Variance ; Animals ; Biological and medical sciences ; Biological Transport - drug effects ; Central nervous system ; Central neurotransmission. Neuromudulation. Pathways and receptors ; Excitatory Amino Acid Antagonists ; Excitatory amino acids ; Fundamental and applied biological sciences. Psychology ; Glutamate ; Glutamates - pharmacokinetics ; Glutamic Acid ; Male ; Potassium - pharmacology ; Rats ; Rats, Sprague-Dawley ; Sodium - pharmacology ; Subcellular Fractions - metabolism ; Transport ; Tritium ; Uptake ; Vertebrates: nervous system and sense organs</subject><ispartof>Journal of neurochemistry, 1993-01, Vol.60 (1), p.167-179</ispartof><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3797-25eea36948de97646a7c695ac4752b11c1601b5d880d9c99bf0b117c00831d403</citedby><cites>FETCH-LOGICAL-c3797-25eea36948de97646a7c695ac4752b11c1601b5d880d9c99bf0b117c00831d403</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1471-4159.1993.tb05835.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1471-4159.1993.tb05835.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,4024,27923,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4512529$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8093259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Robinson, Michael B.</creatorcontrib><creatorcontrib>Sinor, Jeroo D.</creatorcontrib><creatorcontrib>Dowd, Lisa A.</creatorcontrib><creatorcontrib>Kerwin, James F.</creatorcontrib><title>Subtypes of Sodium‐Dependent High‐Affinity L‐[3H]Glutamate Transport Activity: Pharmacologic Specificity and Regulation by Sodium and Potassium</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>: Some data suggest that the sodium‐dependent, high‐affinity L‐glutamate (Glu) transport sites in forebrain are different from those in cerebellum. In the present study, sodium‐dependent transport of L‐[3H]Glu was characterized in cerebellum and cortex. In both cerebellar and cortical tissue, activity was enriched in synaptosomes. Approximately 100 excitatory amino acid analogues were tested as potential inhibitors of transport activity. Many of the compounds tested inhibited transport activity by <65% at 1 mM and were not studied further. One group of compounds exhibited inhibition conforming to theoretical curves with Hill coefficients of 1 and were <10‐fold selective as inhibitors of transport activity. These included three of the putative endogenous substrates for transport: L‐Glu, L‐aspartate, and L‐cysteate. Four of the compounds exhibited inhibition conforming to theoretical curves with Hill coefficients of 1 and were > 10‐fold selective as inhibitors. These included β‐N‐oxalyl‐L‐α,β‐diaminopropionate, α‐methyl‐DL‐glutamate, (2S, 1′S,2′S)‐2‐(carboxycyclopropyl)glycine, and (2S, 1′S,2′S,3′S)‐2‐(2‐carboxy‐3‐methoxymethylcyclopropyl)glycine. Data obtained with a few of the inhibitors were consistent with two sites in one or both of the brain regions. (2S, 1′R,2′R)‐2‐(Carboxycyclopropyl)glycine (L‐CCG‐II) was identified as the most potent (IC50= 5.5 μM) and selective (60–100‐fold) inhibitor of transport activity in cerebellum. One of the potential endogenous substrates, L‐homocysteate, was also a selective inhibitor of cerebellar transport activity. The data for inhibition of transport activity in cortex by both L‐CCG‐II and L‐homocysteate were best fit to two sites. Kainate was equipotent as an inhibitor of transport activity, and in both brain regions the data for inhibition were best fit to two sites. The possibility that there are four subtypes of excitatory amino acid transport is discussed. Altering sodium and potassium levels affects cerebellar and cortical transport activity differently, suggesting that the differences extend to other recognition sites on these transporters.</description><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biological Transport - drug effects</subject><subject>Central nervous system</subject><subject>Central neurotransmission. Neuromudulation. Pathways and receptors</subject><subject>Excitatory Amino Acid Antagonists</subject><subject>Excitatory amino acids</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glutamate</subject><subject>Glutamates - pharmacokinetics</subject><subject>Glutamic Acid</subject><subject>Male</subject><subject>Potassium - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Sodium - pharmacology</subject><subject>Subcellular Fractions - metabolism</subject><subject>Transport</subject><subject>Tritium</subject><subject>Uptake</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVUcFu1DAUtBCobAufgGQhxC3BjuM47gFptS1d0AoqtpwQshzH2XqVxCF2SnPrJ_TCD_IlOGy0d3yx3puZ9-wZAF5jFONw3u1jnDIcpZjyGHNOYl8gmhMa3z8BiyP0FCwQSpKIoDR5Dk6d2yOEszTDJ-AkR5wklC_A7-1Q-LHTDtoKbm1phubPw-OF7nRb6tbDtdndhsayqkxr_Ag3ofhO1j-u6sHLRnoNb3rZus72Hi6VN3eBdA6vb2XfSGVruzMKbjutTGXUpJdtCb_q3VBLb2wLi3Fe-g-4tl46F6oX4Fkla6dfzvcZ-Pbh8ma1jjZfrj6ulptIEcZZlFCtJcl4mpeas_A1yVTGqVQpo0mBscIZwgUt8xyVXHFeVCh0mUIoJ7hMETkDbw9zu97-HLTzojFO6bqWrbaDE4zSJENZGojnB6LqrXO9rkTXm0b2o8BITJmIvZiMF5PxYspEzJmI-yB-NW8ZikaXR-kcQsDfzLh0StZVMFQZd6SlFCc0mWjvD7RfptbjfzxAfPq8whkjfwEGu62s</recordid><startdate>199301</startdate><enddate>199301</enddate><creator>Robinson, Michael B.</creator><creator>Sinor, Jeroo D.</creator><creator>Dowd, Lisa A.</creator><creator>Kerwin, James F.</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><scope>IQODW</scope><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>7X8</scope></search><sort><creationdate>199301</creationdate><title>Subtypes of Sodium‐Dependent High‐Affinity L‐[3H]Glutamate Transport Activity: Pharmacologic Specificity and Regulation by Sodium and Potassium</title><author>Robinson, Michael B. ; Sinor, Jeroo D. ; Dowd, Lisa A. ; Kerwin, James F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3797-25eea36948de97646a7c695ac4752b11c1601b5d880d9c99bf0b117c00831d403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biological Transport - drug effects</topic><topic>Central nervous system</topic><topic>Central neurotransmission. Neuromudulation. Pathways and receptors</topic><topic>Excitatory Amino Acid Antagonists</topic><topic>Excitatory amino acids</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Glutamate</topic><topic>Glutamates - pharmacokinetics</topic><topic>Glutamic Acid</topic><topic>Male</topic><topic>Potassium - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Sodium - pharmacology</topic><topic>Subcellular Fractions - metabolism</topic><topic>Transport</topic><topic>Tritium</topic><topic>Uptake</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Robinson, Michael B.</creatorcontrib><creatorcontrib>Sinor, Jeroo D.</creatorcontrib><creatorcontrib>Dowd, Lisa A.</creatorcontrib><creatorcontrib>Kerwin, James F.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Robinson, Michael B.</au><au>Sinor, Jeroo D.</au><au>Dowd, Lisa A.</au><au>Kerwin, James F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Subtypes of Sodium‐Dependent High‐Affinity L‐[3H]Glutamate Transport Activity: Pharmacologic Specificity and Regulation by Sodium and Potassium</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>1993-01</date><risdate>1993</risdate><volume>60</volume><issue>1</issue><spage>167</spage><epage>179</epage><pages>167-179</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>: Some data suggest that the sodium‐dependent, high‐affinity L‐glutamate (Glu) transport sites in forebrain are different from those in cerebellum. In the present study, sodium‐dependent transport of L‐[3H]Glu was characterized in cerebellum and cortex. In both cerebellar and cortical tissue, activity was enriched in synaptosomes. Approximately 100 excitatory amino acid analogues were tested as potential inhibitors of transport activity. Many of the compounds tested inhibited transport activity by <65% at 1 mM and were not studied further. One group of compounds exhibited inhibition conforming to theoretical curves with Hill coefficients of 1 and were <10‐fold selective as inhibitors of transport activity. These included three of the putative endogenous substrates for transport: L‐Glu, L‐aspartate, and L‐cysteate. Four of the compounds exhibited inhibition conforming to theoretical curves with Hill coefficients of 1 and were > 10‐fold selective as inhibitors. These included β‐N‐oxalyl‐L‐α,β‐diaminopropionate, α‐methyl‐DL‐glutamate, (2S, 1′S,2′S)‐2‐(carboxycyclopropyl)glycine, and (2S, 1′S,2′S,3′S)‐2‐(2‐carboxy‐3‐methoxymethylcyclopropyl)glycine. Data obtained with a few of the inhibitors were consistent with two sites in one or both of the brain regions. (2S, 1′R,2′R)‐2‐(Carboxycyclopropyl)glycine (L‐CCG‐II) was identified as the most potent (IC50= 5.5 μM) and selective (60–100‐fold) inhibitor of transport activity in cerebellum. One of the potential endogenous substrates, L‐homocysteate, was also a selective inhibitor of cerebellar transport activity. The data for inhibition of transport activity in cortex by both L‐CCG‐II and L‐homocysteate were best fit to two sites. Kainate was equipotent as an inhibitor of transport activity, and in both brain regions the data for inhibition were best fit to two sites. The possibility that there are four subtypes of excitatory amino acid transport is discussed. Altering sodium and potassium levels affects cerebellar and cortical transport activity differently, suggesting that the differences extend to other recognition sites on these transporters.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>8093259</pmid><doi>10.1111/j.1471-4159.1993.tb05835.x</doi><tpages>13</tpages></addata></record> |
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| subjects | Analysis of Variance Animals Biological and medical sciences Biological Transport - drug effects Central nervous system Central neurotransmission. Neuromudulation. Pathways and receptors Excitatory Amino Acid Antagonists Excitatory amino acids Fundamental and applied biological sciences. Psychology Glutamate Glutamates - pharmacokinetics Glutamic Acid Male Potassium - pharmacology Rats Rats, Sprague-Dawley Sodium - pharmacology Subcellular Fractions - metabolism Transport Tritium Uptake Vertebrates: nervous system and sense organs |
| title | Subtypes of Sodium‐Dependent High‐Affinity L‐[3H]Glutamate Transport Activity: Pharmacologic Specificity and Regulation by Sodium and Potassium |
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