Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter
We have screened a human substantia nigra cDNA library with probes derived from the rat dopamine transporter. A 3.5-kilobase cDNA clone was isolated and its corresponding gene was located on the distal end of chromosome 5 (5p15.3). This human clone codes for a 620-amino acid protein with a calculate...
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| Veröffentlicht in: | Molecular pharmacology 1992-09, Vol.42 (3), p.383-390 |
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| creator | Giros, B el Mestikawy, S Godinot, N Zheng, K Han, H Yang-Feng, T Caron, M G |
| description | We have screened a human substantia nigra cDNA library with probes derived from the rat dopamine transporter. A 3.5-kilobase
cDNA clone was isolated and its corresponding gene was located on the distal end of chromosome 5 (5p15.3). This human clone
codes for a 620-amino acid protein with a calculated molecular weight of 68,517. Hydropathicity analysis suggests the presence
of 12 putative transmembrane domains, a characteristic feature of sodium-dependent neurotransmitter carriers. The rat and
the human dopamine transporters are 92% homologous. When permanently expressed in mouse fibroblast Ltk- cells, the human clone
is able to induce a saturable, time- and sodium-dependent, dopamine uptake. This transport is blocked by psychostimulant drugs
(cocaine, l- and d-amphetamine, and phenyclidine), neurotoxins (6-hydroxydopamine and N-methyl-4-phenylpyridine (MPP))+),
neurotransmitters (epinephrine, norepinephrine, gamma-aminobutyric acid, and serotonin), antidepressants (amitriptyline, bupropion,
desipramine, mazindol, nomifensine, and nortriptyline), and various uptake inhibitors (mazindol, GBR 12783, GBR 12909, and
amfonelic acid). The rank orders of the Ki values of these substances at the human and the rat dopamine transporters are highly
correlated (r = 0.998). The cloning of DNA human dopamine transporter gene has allowed establishment of a cell line stably
expressing the human dopamine transporter and, for the first time, an extensive characterization of its pharmacology. Furthermore,
these newly developed tools will help in the study of the regulation of dopamine transport in humans and in the clarification
of the potential role of the dopamine transporter in a variety of disease states. |
| format | Article |
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cDNA clone was isolated and its corresponding gene was located on the distal end of chromosome 5 (5p15.3). This human clone
codes for a 620-amino acid protein with a calculated molecular weight of 68,517. Hydropathicity analysis suggests the presence
of 12 putative transmembrane domains, a characteristic feature of sodium-dependent neurotransmitter carriers. The rat and
the human dopamine transporters are 92% homologous. When permanently expressed in mouse fibroblast Ltk- cells, the human clone
is able to induce a saturable, time- and sodium-dependent, dopamine uptake. This transport is blocked by psychostimulant drugs
(cocaine, l- and d-amphetamine, and phenyclidine), neurotoxins (6-hydroxydopamine and N-methyl-4-phenylpyridine (MPP))+),
neurotransmitters (epinephrine, norepinephrine, gamma-aminobutyric acid, and serotonin), antidepressants (amitriptyline, bupropion,
desipramine, mazindol, nomifensine, and nortriptyline), and various uptake inhibitors (mazindol, GBR 12783, GBR 12909, and
amfonelic acid). The rank orders of the Ki values of these substances at the human and the rat dopamine transporters are highly
correlated (r = 0.998). The cloning of DNA human dopamine transporter gene has allowed establishment of a cell line stably
expressing the human dopamine transporter and, for the first time, an extensive characterization of its pharmacology. Furthermore,
these newly developed tools will help in the study of the regulation of dopamine transport in humans and in the clarification
of the potential role of the dopamine transporter in a variety of disease states.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 1406597</identifier><identifier>CODEN: MOPMA3</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Amino Acid Sequence ; Analytical, structural and metabolic biochemistry ; Animals ; Base Sequence ; Binding and carrier proteins ; Biological and medical sciences ; brain ; Carrier Proteins - genetics ; Carrier Proteins - pharmacology ; cDNA ; chromosome 5 ; Chromosomes - physiology ; Clone Cells ; Cloning, Molecular ; DNA - genetics ; DNA - isolation & purification ; DNA Probes ; dopamine ; Dopamine - metabolism ; Dopamine - pharmacokinetics ; Dopamine Plasma Membrane Transport Proteins ; Fundamental and applied biological sciences. Psychology ; genes ; Humans ; localization ; man ; Membrane Glycoproteins ; Membrane Transport Proteins ; Molecular Sequence Data ; Nerve Tissue Proteins ; nucleotide sequence ; pharmacology ; predictions ; Proteins ; Rats ; Substantia Nigra - physiology ; transporter ; Tritium</subject><ispartof>Molecular pharmacology, 1992-09, Vol.42 (3), p.383-390</ispartof><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4361263$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1406597$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Giros, B</creatorcontrib><creatorcontrib>el Mestikawy, S</creatorcontrib><creatorcontrib>Godinot, N</creatorcontrib><creatorcontrib>Zheng, K</creatorcontrib><creatorcontrib>Han, H</creatorcontrib><creatorcontrib>Yang-Feng, T</creatorcontrib><creatorcontrib>Caron, M G</creatorcontrib><title>Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>We have screened a human substantia nigra cDNA library with probes derived from the rat dopamine transporter. A 3.5-kilobase
cDNA clone was isolated and its corresponding gene was located on the distal end of chromosome 5 (5p15.3). This human clone
codes for a 620-amino acid protein with a calculated molecular weight of 68,517. Hydropathicity analysis suggests the presence
of 12 putative transmembrane domains, a characteristic feature of sodium-dependent neurotransmitter carriers. The rat and
the human dopamine transporters are 92% homologous. When permanently expressed in mouse fibroblast Ltk- cells, the human clone
is able to induce a saturable, time- and sodium-dependent, dopamine uptake. This transport is blocked by psychostimulant drugs
(cocaine, l- and d-amphetamine, and phenyclidine), neurotoxins (6-hydroxydopamine and N-methyl-4-phenylpyridine (MPP))+),
neurotransmitters (epinephrine, norepinephrine, gamma-aminobutyric acid, and serotonin), antidepressants (amitriptyline, bupropion,
desipramine, mazindol, nomifensine, and nortriptyline), and various uptake inhibitors (mazindol, GBR 12783, GBR 12909, and
amfonelic acid). The rank orders of the Ki values of these substances at the human and the rat dopamine transporters are highly
correlated (r = 0.998). The cloning of DNA human dopamine transporter gene has allowed establishment of a cell line stably
expressing the human dopamine transporter and, for the first time, an extensive characterization of its pharmacology. Furthermore,
these newly developed tools will help in the study of the regulation of dopamine transport in humans and in the clarification
of the potential role of the dopamine transporter in a variety of disease states.</description><subject>Amino Acid Sequence</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Binding and carrier proteins</subject><subject>Biological and medical sciences</subject><subject>brain</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - pharmacology</subject><subject>cDNA</subject><subject>chromosome 5</subject><subject>Chromosomes - physiology</subject><subject>Clone Cells</subject><subject>Cloning, Molecular</subject><subject>DNA - genetics</subject><subject>DNA - isolation & purification</subject><subject>DNA Probes</subject><subject>dopamine</subject><subject>Dopamine - metabolism</subject><subject>Dopamine - pharmacokinetics</subject><subject>Dopamine Plasma Membrane Transport Proteins</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>genes</subject><subject>Humans</subject><subject>localization</subject><subject>man</subject><subject>Membrane Glycoproteins</subject><subject>Membrane Transport Proteins</subject><subject>Molecular Sequence Data</subject><subject>Nerve Tissue Proteins</subject><subject>nucleotide sequence</subject><subject>pharmacology</subject><subject>predictions</subject><subject>Proteins</subject><subject>Rats</subject><subject>Substantia Nigra - physiology</subject><subject>transporter</subject><subject>Tritium</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkFtLxDAQhYMo67r6E4Q8qE9byKXp5VEWb7Dgi4JvZZombaRJatIi-usNuIjMwzBzvjkw5witqWA0I5TSY7QmhBVZVYu3U3QW4zshNBcVWaEVzUkh6nKN9G70zrh-i6cBggXpR98bCSOWaQY5q2C-YTbebTG4Lm2Dtz56qzDEaHpnlZux13geFB4WCw53fgJrnMJzABcnH5LHOTrRMEZ1cegb9Hp_97J7zPbPD0-72302sLqYM6CsK1tOOlJq1ZKOdqrQVOgaaM4ZpCoFl0ITwTtJOW_btlJU0jrPNas44xt08-s7Bf-xqDg31kSpxhGc8ktsaJGns7pM4OUBXFqrumYKxkL4ag7BJP3qoENMaej0ijTxD8t5QVnBE3b9iw2mHz5NUM2_GBPGGt7wivMfC357zg</recordid><startdate>19920901</startdate><enddate>19920901</enddate><creator>Giros, B</creator><creator>el Mestikawy, S</creator><creator>Godinot, N</creator><creator>Zheng, K</creator><creator>Han, H</creator><creator>Yang-Feng, T</creator><creator>Caron, M G</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QL</scope><scope>7T3</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>M81</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>19920901</creationdate><title>Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter</title><author>Giros, B ; el Mestikawy, S ; Godinot, N ; Zheng, K ; Han, H ; Yang-Feng, T ; Caron, M G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h296t-a12d7b30d07feb0d1de6f15f9a1432a2a2753c5f053dc133bbb8e1c1944f28323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Amino Acid Sequence</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Binding and carrier proteins</topic><topic>Biological and medical sciences</topic><topic>brain</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - pharmacology</topic><topic>cDNA</topic><topic>chromosome 5</topic><topic>Chromosomes - physiology</topic><topic>Clone Cells</topic><topic>Cloning, Molecular</topic><topic>DNA - genetics</topic><topic>DNA - isolation & purification</topic><topic>DNA Probes</topic><topic>dopamine</topic><topic>Dopamine - metabolism</topic><topic>Dopamine - pharmacokinetics</topic><topic>Dopamine Plasma Membrane Transport Proteins</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>genes</topic><topic>Humans</topic><topic>localization</topic><topic>man</topic><topic>Membrane Glycoproteins</topic><topic>Membrane Transport Proteins</topic><topic>Molecular Sequence Data</topic><topic>Nerve Tissue Proteins</topic><topic>nucleotide sequence</topic><topic>pharmacology</topic><topic>predictions</topic><topic>Proteins</topic><topic>Rats</topic><topic>Substantia Nigra - physiology</topic><topic>transporter</topic><topic>Tritium</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Giros, B</creatorcontrib><creatorcontrib>el Mestikawy, S</creatorcontrib><creatorcontrib>Godinot, N</creatorcontrib><creatorcontrib>Zheng, K</creatorcontrib><creatorcontrib>Han, H</creatorcontrib><creatorcontrib>Yang-Feng, T</creatorcontrib><creatorcontrib>Caron, M G</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>Bacteriology Abstracts (Microbiology B)</collection><collection>Human Genome Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biochemistry Abstracts 3</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Giros, B</au><au>el Mestikawy, S</au><au>Godinot, N</au><au>Zheng, K</au><au>Han, H</au><au>Yang-Feng, T</au><au>Caron, M G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1992-09-01</date><risdate>1992</risdate><volume>42</volume><issue>3</issue><spage>383</spage><epage>390</epage><pages>383-390</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><coden>MOPMA3</coden><abstract>We have screened a human substantia nigra cDNA library with probes derived from the rat dopamine transporter. A 3.5-kilobase
cDNA clone was isolated and its corresponding gene was located on the distal end of chromosome 5 (5p15.3). This human clone
codes for a 620-amino acid protein with a calculated molecular weight of 68,517. Hydropathicity analysis suggests the presence
of 12 putative transmembrane domains, a characteristic feature of sodium-dependent neurotransmitter carriers. The rat and
the human dopamine transporters are 92% homologous. When permanently expressed in mouse fibroblast Ltk- cells, the human clone
is able to induce a saturable, time- and sodium-dependent, dopamine uptake. This transport is blocked by psychostimulant drugs
(cocaine, l- and d-amphetamine, and phenyclidine), neurotoxins (6-hydroxydopamine and N-methyl-4-phenylpyridine (MPP))+),
neurotransmitters (epinephrine, norepinephrine, gamma-aminobutyric acid, and serotonin), antidepressants (amitriptyline, bupropion,
desipramine, mazindol, nomifensine, and nortriptyline), and various uptake inhibitors (mazindol, GBR 12783, GBR 12909, and
amfonelic acid). The rank orders of the Ki values of these substances at the human and the rat dopamine transporters are highly
correlated (r = 0.998). The cloning of DNA human dopamine transporter gene has allowed establishment of a cell line stably
expressing the human dopamine transporter and, for the first time, an extensive characterization of its pharmacology. Furthermore,
these newly developed tools will help in the study of the regulation of dopamine transport in humans and in the clarification
of the potential role of the dopamine transporter in a variety of disease states.</abstract><cop>Bethesda, MD</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>1406597</pmid><tpages>8</tpages></addata></record> |
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| identifier | ISSN: 0026-895X |
| ispartof | Molecular pharmacology, 1992-09, Vol.42 (3), p.383-390 |
| issn | 0026-895X 1521-0111 |
| language | eng |
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| subjects | Amino Acid Sequence Analytical, structural and metabolic biochemistry Animals Base Sequence Binding and carrier proteins Biological and medical sciences brain Carrier Proteins - genetics Carrier Proteins - pharmacology cDNA chromosome 5 Chromosomes - physiology Clone Cells Cloning, Molecular DNA - genetics DNA - isolation & purification DNA Probes dopamine Dopamine - metabolism Dopamine - pharmacokinetics Dopamine Plasma Membrane Transport Proteins Fundamental and applied biological sciences. Psychology genes Humans localization man Membrane Glycoproteins Membrane Transport Proteins Molecular Sequence Data Nerve Tissue Proteins nucleotide sequence pharmacology predictions Proteins Rats Substantia Nigra - physiology transporter Tritium |
| title | Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter |
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