Source:http://linkedlifedata.com/resource/pubmed/id/12480177
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1-2
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| pubmed:dateCreated |
2002-12-13
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| pubmed:abstractText |
Highly conserved motifs in the monoamine transporters, e.g. the human norepinephrine transporter (hNET) GXXXRXG motif which was the focus of the present study, are likely to be important structural features in determining function. This motif was investigated by mutating the glycines to glutamate (causing loss of function) and alanine, and the arginine to glycine. The effects of hG117A, hR121G and hG123A mutations on function were examined in COS-7 cells and compared to hNET. Substrate K(m) values were decreased for hG117A and hG123A, and their K(i) values for inhibition of [3H]nisoxetine binding were decreased 3-4-fold and 4-6-fold, respectively. Transporter turnover was reduced to 65% of hNET for hG117A and hR121G and to 28% for hG123A, suggesting that substrate translocation is impaired. K(i) values of nisoxetine and desipramine for inhibition of [3H]norepinephrine uptake were increased by 5-fold for hG117A, with no change for cocaine. The K(i) value of cocaine was increased by 3-fold for hG123A, with no change for nisoxetine and desipramine. However, there were no effects of the mutations on the K(d) of [3H]nisoxetine binding or K(i) values of desipramine or cocaine for inhibition of [3H]nisoxetine binding. Hence, glycine residues of the GXXXRXG motif are important determinants of NET expression and function, while the arginine residue does not have a major role. This study also showed that antidepressants and psychostimulants have different NET binding sites and provided the first evidence that different sites on the NET are involved in the binding of inhibitors and their competitive inhibition of substrate uptake.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Arginine,
http://linkedlifedata.com/resource/pubmed/chemical/Cocaine,
http://linkedlifedata.com/resource/pubmed/chemical/Desipramine,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Fluoxetine,
http://linkedlifedata.com/resource/pubmed/chemical/Glycine,
http://linkedlifedata.com/resource/pubmed/chemical/Norepinephrine,
http://linkedlifedata.com/resource/pubmed/chemical/Norepinephrine Plasma Membrane...,
http://linkedlifedata.com/resource/pubmed/chemical/SLC6A2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Symporters,
http://linkedlifedata.com/resource/pubmed/chemical/Vasoconstrictor Agents,
http://linkedlifedata.com/resource/pubmed/chemical/nisoxetine
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| pubmed:status |
MEDLINE
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| pubmed:month |
Dec
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| pubmed:issn |
0169-328X
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
108
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
40-50
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| pubmed:dateRevised |
2006-11-15
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| pubmed:meshHeading |
pubmed-meshheading:12480177-Amino Acid Motifs,
pubmed-meshheading:12480177-Amino Acid Sequence,
pubmed-meshheading:12480177-Arginine,
pubmed-meshheading:12480177-Binding Sites,
pubmed-meshheading:12480177-Cell Line,
pubmed-meshheading:12480177-Cocaine,
pubmed-meshheading:12480177-Conserved Sequence,
pubmed-meshheading:12480177-Desipramine,
pubmed-meshheading:12480177-Enzyme Inhibitors,
pubmed-meshheading:12480177-Fluoxetine,
pubmed-meshheading:12480177-Glycine,
pubmed-meshheading:12480177-Humans,
pubmed-meshheading:12480177-Mutagenesis, Site-Directed,
pubmed-meshheading:12480177-Norepinephrine,
pubmed-meshheading:12480177-Norepinephrine Plasma Membrane Transport Proteins,
pubmed-meshheading:12480177-Protein Binding,
pubmed-meshheading:12480177-Sequence Alignment,
pubmed-meshheading:12480177-Symporters,
pubmed-meshheading:12480177-Vasoconstrictor Agents
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| pubmed:year |
2002
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| pubmed:articleTitle |
The role of the conserved GXXXRXG motif in the expression and function of the human norepinephrine transporter.
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| pubmed:affiliation |
Department of Physiology and Pharmacology, School of Biomedical Sciences, The University of Queensland, Brisbane, Qld 4072, Australia.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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