Pharmacological properties of the naturally occurring Ala457Pro variant of the human norepinephrine transporter

Paczkowski, Filip A., Bonisch, Heinz and Bryan-Lluka, Lesley J. (2002) Pharmacological properties of the naturally occurring Ala457Pro variant of the human norepinephrine transporter. Pharmacogenetics, 12 2: 165-173. doi:10.1097/00008571-200203000-00010

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Author Paczkowski, Filip A.
Bonisch, Heinz
Bryan-Lluka, Lesley J.
Title Pharmacological properties of the naturally occurring Ala457Pro variant of the human norepinephrine transporter
Journal name Pharmacogenetics   Check publisher's open access policy
ISSN 0960-314X
Publication date 2002-01-01
Sub-type Article (original research)
DOI 10.1097/00008571-200203000-00010
Open Access Status Not Open Access
Volume 12
Issue 2
Start page 165
End page 173
Total pages 9
Editor Y. Yamazoe
W. E. Evans
M. Eichelbaum
Place of publication United States
Publisher Lippincott Williams & Wilkins
Language eng
Subject C1
1115 Pharmacology and Pharmaceutical Sciences
Abstract Recently, another reserach group has reported an almost complete loss of function of the human norepinephrine transporter (hNET) in patients who had orthostatic Intolerance and who were heterozygous for a guanine to cytosine exchange, resulting in a hNET Ala(457) Pro variant. To explore the reason for the deficiency in NET function, we compared in detail the pharmacology of the Ala(457) Pro variant with that of the wild-type hNET in COS-7 cells transiently transfected with hNET or Ala(457)Pro cDNA. Compared to the wild-type hNET, the Ala(457)Pro variant exhibited a five-fold higher affinity for cocaine, but a twofold lower affinity for the NET inhibitor nisoxetine, and an unchanged affinity for the antidepressant desipramine. Plasma membrane expression (measured as B-max of [H-3]nisoxetine binding) of the Ala(457)Pro variant was only 40% of that of the wild-type hNET. The Ala(457)Pro variant showed a six- to 10-fold decrease in affinity for the substrates dopamine and 1-methyl-4-phenylpyridinium (MPP+). Compared with the wild-type hNET, the maximum rate (V-max) of norepinephrine uptake by the Ala(457) Pro variant was slightly reduced, whereas the turnover number (calculated from V-max/B-max) was approximately two-fold higher. However, the Ala(457) Pro variant exhibited a 50-fold higher K-m (i.e. lower apparent affinity) for norepinephrine than the wild-type hNET. Thus, the previously reported loss of function of the Ala(457)Pro variant associated with orthostatic intolerance is only partly due to a reduction in plasma membrane expression of the transporter, and is mainly caused by the pronounced reduction in the apparent affinity of norepinephrine.
Keyword Genetics & Heredity
Pharmacology & Pharmacy
Human Norepinephrine Transporter Variant
Norepinephrine Transport Kinetics
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 11 Apr 2006, 02:08:27 EST