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Titolo:
Cloning of dopamine, norepinephrine and serotonin transporters from monkeybrain: relevance to cocaine sensitivity
Autore:
Miller, GM; Yatin, SM; De La Garza, R; Goulet, M; Madras, BK;
Indirizzi:
Harvard Univ, Sch Med, Div Neurochem, New England Reg Primate Res Ctr, Southborough, MA 01772 USA Harvard Univ Southborough MA USA 01772 es Ctr, Southborough, MA 01772 USA
Titolo Testata:
MOLECULAR BRAIN RESEARCH
fascicolo: 1, volume: 87, anno: 2001,
pagine: 124 - 143
SICI:
0169-328X(20010219)87:1<124:CODNAS>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
DEFICIT HYPERACTIVITY DISORDER; I-123 BETA-CIT; EMISSION COMPUTED-TOMOGRAPHY; CENTRAL-NERVOUS-SYSTEM; NONHUMAN-PRIMATES; CODING REGION; PHORBOL ESTERS; RHESUS-MONKEYS; NEUROTRANSMITTER TRANSPORTERS; NORADRENALINE TRANSPORTER;
Keywords:
monoamine; phosphorylation; addiction; polymorphism; ADHD; reuptake;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
95
Recensione:
Indirizzi per estratti:
Indirizzo: Madras, BK Harvard Univ, Sch Med, Div Neurochem, New England Reg Primate Res Ctr, 1 Pine Hill Dr, Southborough, MA 01772 USA Harvard Univ 1 Pine HillDr Southborough MA USA 01772 01772 USA
Citazione:
G.M. Miller et al., "Cloning of dopamine, norepinephrine and serotonin transporters from monkeybrain: relevance to cocaine sensitivity", MOL BRAIN R, 87(1), 2001, pp. 124-143

Abstract

We used RT-PCR to clone monoamine transporters from Macaca mulatta, Macacafasicularis, is and Saimiri sciureus (dopamine transporter; DAT) and Macaca mulatta (norepinephrine transporter; NET and serotonin transporter; SERT). Monkey DAT, NET and SERT proteins were >98% homologous to human and, whenexpressed in HEK-293 cells, displayed drug affinities and uptake kinetics that were highly correlated with monkey brain or human monoamine transporters. In contrast to reports of other species, we discovered double (leucine for phenylalanine 143 and arginine for glutamine 509; Variant I) and single(proline for leucine 355; Variant LI) amino acid variants of DAT. Variant I displayed dopamine transport kinetics and binding affinities for various DAT blockers (including cocaine) versus [H-3] CFT (WIN 35, 428) that were identical to wild-type DAT (n = 7 drugs; r(2)=0.991). However, we detected asix-fold difference in the affinity of cocaine versus [H-3] cocaine between Variant I (IC50: 488 +/- 102 nM, SEM, n = 3) and wild-type DAT (IC50: 79 /- 8.2 nM, n = 3, P < 0.05). Variant II was localized intracellularly in HEK-293 cells, as detected by confocal microscopy, and had very low levels of binding and dopamine transport. Also discovered was a novel exon 5 splicevariant of NET that displayed very low levels of transport and did not bind cocaine. With NetPhos analysis, we detected a number of highly conserved putative phosphorylation sites on extracellular as well as intracellular loops of the DAT, NET, and SERT, which may be functional for internalized transporters. The homology and functional similarity of human and monkey monoamine transporters further support the value of primates in investigating the role of monoamine transporters in substance abuse mechanisms, neuropsychiatric disorders and development of diagnostic and therapeutic agents. (C) 2001 Elsevier Science B.V. All rights reserved.

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Documento generato il 19/01/20 alle ore 20:09:01