| http://purl.uniprot.org/citations/12805287 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/12805287 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/12805287 | http://purl.org/dc/terms/identifier | "doi:10.1523/jneurosci.23-11-04470.2003"xsd:string |
| http://purl.uniprot.org/citations/12805287 | http://purl.uniprot.org/core/author | "Blakely R.D."xsd:string |
| http://purl.uniprot.org/citations/12805287 | http://purl.uniprot.org/core/author | "Robertson D."xsd:string |
| http://purl.uniprot.org/citations/12805287 | http://purl.uniprot.org/core/author | "Hahn M.K."xsd:string |
| http://purl.uniprot.org/citations/12805287 | http://purl.uniprot.org/core/date | "2003"xsd:gYear |
| http://purl.uniprot.org/citations/12805287 | http://purl.uniprot.org/core/name | "J Neurosci"xsd:string |
| http://purl.uniprot.org/citations/12805287 | http://purl.uniprot.org/core/pages | "4470-4478"xsd:string |
| http://purl.uniprot.org/citations/12805287 | http://purl.uniprot.org/core/title | "A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters."xsd:string |
| http://purl.uniprot.org/citations/12805287 | http://purl.uniprot.org/core/volume | "23"xsd:string |
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