Source:http://linkedlifedata.com/resource/pubmed/id/12805287
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
11
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| pubmed:dateCreated |
2003-6-13
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| pubmed:abstractText |
The norepinephrine transporter (NET) mediates reuptake of norepinephrine released from neurons, and, as such, it is an important regulator of noradrenergic neurotransmission. Recently, our laboratory reported a polymorphism in the human NET (hNET) gene A457P in an individual with the autonomic disorder orthostatic intolerance (OI). The presence of the hNET-A457P allele tracked with elevated heart rates and plasma NE levels in family members. hNET-A457P lacks >98% transport activity in several heterologous expression systems. In the present work, Western blot and biotinylation analyses performed in transiently transfected COS-7 cells revealed impairment in processing of hNET-A457P to the fully glycosylated form and a decrease in surface expression to approximately 30% of hNET-wild type (hNET-wt). Because the hNET-A457P mutation is carried on a single allele in OI subjects, we examined the influence of cotransfection of hNET-wt and hNET-A457P and found that hNET-A457P exerts a dominant-negative effect on hNET-wt uptake activity. Experiments to determine oligomerization as a potential mechanism of the dominant-negative effect demonstrated that hNET-A457P coimmunoprecipitates with, and diminishes surface expression of, hNET-wt. These results reveal that hNET-A457P causes a conformational disruption that interferes with transporter biosynthetic progression and trafficking of both the mutant transporter and hNET-wt. These results elucidate a molecular mechanism for the disrupted NE homeostasis and cardiovascular function evident in OI patients with the hNET-A457P mutation.
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| pubmed:grant | |
| pubmed:keyword | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:month |
Jun
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| pubmed:issn |
1529-2401
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:day |
1
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| pubmed:volume |
23
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
4470-8
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| pubmed:dateRevised |
2007-11-14
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| pubmed:meshHeading |
pubmed-meshheading:12805287-Amino Acid Substitution,
pubmed-meshheading:12805287-Animals,
pubmed-meshheading:12805287-Autonomic Nervous System Diseases,
pubmed-meshheading:12805287-Binding, Competitive,
pubmed-meshheading:12805287-Binding Sites,
pubmed-meshheading:12805287-Blotting, Western,
pubmed-meshheading:12805287-COS Cells,
pubmed-meshheading:12805287-Cell Membrane,
pubmed-meshheading:12805287-Genes, Dominant,
pubmed-meshheading:12805287-Glycosylation,
pubmed-meshheading:12805287-Humans,
pubmed-meshheading:12805287-Mutation,
pubmed-meshheading:12805287-Norepinephrine Plasma Membrane Transport Proteins,
pubmed-meshheading:12805287-Posture,
pubmed-meshheading:12805287-Precipitin Tests,
pubmed-meshheading:12805287-Protein Binding,
pubmed-meshheading:12805287-Protein Processing, Post-Translational,
pubmed-meshheading:12805287-Protein Transport,
pubmed-meshheading:12805287-Symporters,
pubmed-meshheading:12805287-Transfection
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| pubmed:year |
2003
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| pubmed:articleTitle |
A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters.
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| pubmed:affiliation |
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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