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Titolo:
Pharmacological properties of naturally occurring variants of the human norepinephrine transporter
Autore:
Runkel, F; Bruss, M; Nothen, MM; Stober, G; Propping, P; Bonisch, H;
Indirizzi:
Univ Bonn, Inst Pharmacol & Toxicol, D-53113 Bonn, Germany Univ Bonn Bonn Germany D-53113 harmacol & Toxicol, D-53113 Bonn, Germany Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany Univ Bonn Bonn GermanyD-5300 nn, Inst Human Genet, D-5300 Bonn, Germany Univ Wurzburg, Dept Psychiat, D-97070 Wurzburg, Germany Univ Wurzburg Wurzburg Germany D-97070 ychiat, D-97070 Wurzburg, Germany
Titolo Testata:
PHARMACOGENETICS
fascicolo: 5, volume: 10, anno: 2000,
pagine: 397 - 405
SICI:
0960-314X(200007)10:5<397:PPONOV>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
SYMPATHETIC-NERVE ACTIVITY; SEROTONIN TRANSPORTER; DOPAMINE TRANSPORTER; MOLECULAR-CLONING; NORADRENALINE TRANSPORTER; NEUROTRANSMITTER TRANSPORTERS; FUNCTIONAL EXPRESSION; COCAINE BINDING; GENE; DESIPRAMINE;
Keywords:
human norepinephrine transporter variants; norepinephrine transport kinetics; hNET; desipramine;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Bonisch, H Univ Bonn, Inst Pharmacol & Toxicol, Reuterstr 2B, D-53113 Bonn, Germany Univ Bonn Reuterstr 2B Bonn Germany D-53113 3113 Bonn, Germany
Citazione:
F. Runkel et al., "Pharmacological properties of naturally occurring variants of the human norepinephrine transporter", PHARMACOGEN, 10(5), 2000, pp. 397-405

Abstract

The human norepinephrine transporter (hNET) gene has five sequence polymorphisms that predict amino acid substitutions in the transporter protein: Val(69)Ile, Thr(99)Ile, Val(245)Ile, Val(449)Ile, and Gly(478)Ser. In order to functionally characterize the naturally occurring transporter variants, we used site-directed mutagenesis to establish the hNET variants and compared some basic pharmacological properties (uptake of norepinephrine and its inhibition by the tricyclic antidepressant desipramine) in COS-7 cells transiently expressing variant hNETs and wild-type hNET. None of the hNET variants displayed changes in the potency (Ki) of desipramine for inhibition of norepinephrine uptake. Furthermore, variants Val(69)Ile, Thr(99)Ile, Val(245)Ile, and Val(449)Ile did not affect kinetic constants (K-m, V-max) of norepinephrine uptake, However, COS-7 cells expressing the hNET variant Gly(478)Ser displayed an approximately four-fold increase in the K-m for norepinephrine, while the V-max was unaffected, The increase in the K-m, which is equivalent to a four-fold reduction in the affinity of the variant hNET for its natural substrate norepinephrine, indicates that the glycine in position478 is part of a substrate recognition domain, The reduced clearance of released norepinephrine by reuptake through the Gly(478)Ser variant might cause an increase in the synaptic and the circulating concentration of norepinephrine. Elevated norepinephrine concentrations have been associated with human diseases and it will be interesting to explore a possible contributionby the Gly(478)Ser variant to certain desease states, Pharmacogenetics 10:397-405 (C) 2000 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 17/01/21 alle ore 18:12:26