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Titolo:
Protein tyrosine kinase inhibitors alter human dopamine transporter activity in Xenopus oocytes
Autore:
Doolen, S; Zahniser, NR;
Indirizzi:
Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA Univ Colorado Denver CO USA 80262 r, Dept Pharmacol, Denver, CO 80262 USA Univ Colorado, Hlth Sci Ctr, Program Neurosci, Denver, CO 80262 USA Univ Colorado Denver CO USA 80262 Program Neurosci, Denver, CO 80262 USA
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 296, anno: 2001,
pagine: 931 - 938
SICI:
0022-3565(200103)296:3<931:PTKIAH>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
FUNCTIONAL REGULATION; PHORBOL ESTERS; NEUROTRANSMITTER TRANSPORTERS; SURFACE EXPRESSION; PHOSPHORYLATION; TRAFFICKING; ACTIVATION; NEURONS; BINDING; CARRIER;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
36
Recensione:
Indirizzi per estratti:
Indirizzo: Doolen, S Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, 4200 E 9th Ave,Box C-236, Denver, CO 80262 USA Univ Colorado 4200 E 9th Ave,Box C-236 Denver CO USA 80262 2 USA
Citazione:
S. Doolen e N.R. Zahniser, "Protein tyrosine kinase inhibitors alter human dopamine transporter activity in Xenopus oocytes", J PHARM EXP, 296(3), 2001, pp. 931-938

Abstract

The dopamine (DA) transporter (DAT) regulates dopaminergic synaptic transmission by controlling extracellular levels of DA. Thus, understanding signaling mechanisms that alter DAT function is critical for understanding dopaminergic neurotransmission. We have expressed the human DAT (hDAT) in Xenopus laevis oocytes to test the hypothesis that protein tyrosine kinases (PTKs) acutely regulate DAT function by altering cell surface expression of the transporter. Using a relatively high concentration of DA (10 muM), we foundthat several PTK inhibitors, namely, genistein, lavendustin A, and tyrphostin 25 (10 muM), decreased DA uptake velocity by 58, 41, and 30% of control, respectively. Furthermore, genistein potently inhibited DA uptake with a K-i = 68 nM. Kinetic analysis confirmed that genistein decreased the V-max of the DAT, with no change in K-m. The effects of PTK inhibition on hDAT-associated currents were also measured. All three PTK inhibitors attenuated substrate transport-associated currents to similar extents as DA uptake. In contrast, the potent Src inhibitor 4-amino-5-(4-chlorophenyl)- 7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2) did not significantly inhibit either DA uptake or transport-associated currents. PTK inhibitors decreased hDAT-associated leak currents, however in a more variable manner than for uptake and transport-associated currents. Genistein also decreased cell surface bindingof [H-3] WIN 35,428 to hDAT by 48% of control. Together, these data provide several lines of evidence suggesting that PTK inhibition rapidly reduces hDAT activity via redistribution of the transporter away from the cell surface. Thus, PTKs likely represent another component of cellular signaling cascades that acutely regulate neurotransmitter transporters.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/09/20 alle ore 07:54:40