Regulation of dopamine transporter trafficking by intracellular amphetamine.

Kristopher M Kahlig; Brandon J Lute; Yuqiang Wei; Claus Juul Løland; Ulrik Gether; Jonathan A Javitch; Aurelio Galli

doi:10.1124/mol.106.023952

Regulation of dopamine transporter trafficking by intracellular amphetamine.

Kristopher M Kahlig, Brandon J Lute, Yuqiang Wei, Claus Juul Løland, Ulrik Gether, Jonathan A Javitch, Aurelio Galli

Institut for Neurovidenskab

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

62 Citationer (Scopus)

Abstract

Udgivelsesdato: 2006-Aug

Originalsprog	Engelsk
Tidsskrift	Molecular Pharmacology
Vol/bind	70
Udgave nummer	2
Sider (fra-til)	542-8
Antal sider	6
ISSN	0026-895X
DOI	https://doi.org/10.1124/mol.106.023952
Status	Udgivet - 2006

Bibliografisk note

Keywords: Amphetamine; Cells, Cultured; Dopamine Plasma Membrane Transport Proteins; Humans; Protein Conformation; Protein Transport; Zinc

Adgang til dokumentet

10.1124/mol.106.023952

Citationsformater

@article{ed36d00075ac11dd81b0000ea68e967b,

title = "Regulation of dopamine transporter trafficking by intracellular amphetamine.",

abstract = "The dopamine (DA) transporter (DAT) mediates the removal of released DA. DAT is the major molecular target responsible for the rewarding properties and abuse potential of the psychostimulant amphetamine (AMPH). AMPH has been shown to reduce the number of DATs at the cell surface, and this AMPH-induced cell surface DAT redistribution may result in long-lasting changes in DA homeostasis. The molecular mechanism by which AMPH induces trafficking is not clear. Because AMPH is a substrate, we do not know whether extracellular AMPH stimulates trafficking through its interaction with DAT and subsequent alteration in DAT function, thereby triggering intracellular signaling or whether AMPH must be transported and then act intracellularly. In agreement with our previous studies, extracellular AMPH caused cytosolic redistribution of the wild-type human DAT (WT-hDAT). However, AMPH did not induce cytosolic redistribution in an uptake-impaired hDAT (Y335A-hDAT) that still binds AMPH. The divalent cation zinc (Zn(2+)) inhibits WT-hDAT activity, but it restores Y335A-hDAT uptake. Coadministration of Zn(2+) and AMPH consistently reduced WT-hDAT trafficking but stimulated cytosolic redistribution of Y335A-hDAT. Furthermore, direct intracellular application of AMPH, via a whole-cell patch pipette, stimulated the trafficking of Y335A-hDAT. Taken together, these data suggest that the DAT transport cycle is not required for AMPH-induced down-regulation and that an increase of intracellular AMPH is an essential component of DAT redistribution.",

author = "Kahlig, {Kristopher M} and Lute, {Brandon J} and Yuqiang Wei and L{\o}land, {Claus Juul} and Ulrik Gether and Javitch, {Jonathan A} and Aurelio Galli",

note = "Keywords: Amphetamine; Cells, Cultured; Dopamine Plasma Membrane Transport Proteins; Humans; Protein Conformation; Protein Transport; Zinc",

year = "2006",

doi = "10.1124/mol.106.023952",

language = "English",

volume = "70",

pages = "542--8",

journal = "Molecular Pharmacology",

issn = "0026-895X",

publisher = "American Society for Pharmacology and Experimental Therapeutics",

number = "2",

}

TY - JOUR

T1 - Regulation of dopamine transporter trafficking by intracellular amphetamine.

AU - Kahlig, Kristopher M

AU - Lute, Brandon J

AU - Wei, Yuqiang

AU - Løland, Claus Juul

AU - Gether, Ulrik

AU - Javitch, Jonathan A

AU - Galli, Aurelio

N1 - Keywords: Amphetamine; Cells, Cultured; Dopamine Plasma Membrane Transport Proteins; Humans; Protein Conformation; Protein Transport; Zinc

PY - 2006

Y1 - 2006

N2 - The dopamine (DA) transporter (DAT) mediates the removal of released DA. DAT is the major molecular target responsible for the rewarding properties and abuse potential of the psychostimulant amphetamine (AMPH). AMPH has been shown to reduce the number of DATs at the cell surface, and this AMPH-induced cell surface DAT redistribution may result in long-lasting changes in DA homeostasis. The molecular mechanism by which AMPH induces trafficking is not clear. Because AMPH is a substrate, we do not know whether extracellular AMPH stimulates trafficking through its interaction with DAT and subsequent alteration in DAT function, thereby triggering intracellular signaling or whether AMPH must be transported and then act intracellularly. In agreement with our previous studies, extracellular AMPH caused cytosolic redistribution of the wild-type human DAT (WT-hDAT). However, AMPH did not induce cytosolic redistribution in an uptake-impaired hDAT (Y335A-hDAT) that still binds AMPH. The divalent cation zinc (Zn(2+)) inhibits WT-hDAT activity, but it restores Y335A-hDAT uptake. Coadministration of Zn(2+) and AMPH consistently reduced WT-hDAT trafficking but stimulated cytosolic redistribution of Y335A-hDAT. Furthermore, direct intracellular application of AMPH, via a whole-cell patch pipette, stimulated the trafficking of Y335A-hDAT. Taken together, these data suggest that the DAT transport cycle is not required for AMPH-induced down-regulation and that an increase of intracellular AMPH is an essential component of DAT redistribution.

AB - The dopamine (DA) transporter (DAT) mediates the removal of released DA. DAT is the major molecular target responsible for the rewarding properties and abuse potential of the psychostimulant amphetamine (AMPH). AMPH has been shown to reduce the number of DATs at the cell surface, and this AMPH-induced cell surface DAT redistribution may result in long-lasting changes in DA homeostasis. The molecular mechanism by which AMPH induces trafficking is not clear. Because AMPH is a substrate, we do not know whether extracellular AMPH stimulates trafficking through its interaction with DAT and subsequent alteration in DAT function, thereby triggering intracellular signaling or whether AMPH must be transported and then act intracellularly. In agreement with our previous studies, extracellular AMPH caused cytosolic redistribution of the wild-type human DAT (WT-hDAT). However, AMPH did not induce cytosolic redistribution in an uptake-impaired hDAT (Y335A-hDAT) that still binds AMPH. The divalent cation zinc (Zn(2+)) inhibits WT-hDAT activity, but it restores Y335A-hDAT uptake. Coadministration of Zn(2+) and AMPH consistently reduced WT-hDAT trafficking but stimulated cytosolic redistribution of Y335A-hDAT. Furthermore, direct intracellular application of AMPH, via a whole-cell patch pipette, stimulated the trafficking of Y335A-hDAT. Taken together, these data suggest that the DAT transport cycle is not required for AMPH-induced down-regulation and that an increase of intracellular AMPH is an essential component of DAT redistribution.

U2 - 10.1124/mol.106.023952

DO - 10.1124/mol.106.023952

M3 - Journal article

C2 - 16684900

SN - 0026-895X

VL - 70

SP - 542

EP - 548

JO - Molecular Pharmacology

JF - Molecular Pharmacology

IS - 2

ER -