title: Structural analysis of dopamine- and amphetamine-induced depolarization currents in the human dopamine transporter.
abstract: Amphetamine (AMPH) induces depolarizing currents through the human dopamine transporter (hDAT). Recently we discovered that the S(+) enantiomer of AMPH induces a current through hDAT that persists long after its removal from the external milieu. The persistent current is less prominent for R(-)AMPH and essentially absent for dopamine (DA)-induced currents. Related agents such as methamphetamine also exhibit persistent currents, which are present in both frog oocyte and mammalian HEK expression systems. Here, we study hDAT-expressing Xenopus laevis oocytes voltage-clamped and exposed from outside to DA, S(+)AMPH, R(-)AMPH, and related synthesized compounds, including stereoisomers. The goal of the study was to determine how structural transitioning from dopamine to amphetamine influences hDAT potency and action. At saturating concentrations, S(+)AMPH or R(-)AMPH induce a sharply rising depolarizing current from -60 mV that is comparable in amplitude to DA-induced currents. The magnitude and duration of the currents and the presence or absence of persistent currents depend on the concentration, duration of exposure, and chemical structure and enantiomeric versions of the agents.
authors.affiliation: †Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, United States.|§Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221004, People's Republic of China.
authors.forename: Qiong-Yao
authors.initials: QY
authors.lastname: Tang
authors.affiliation: ‡Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia 23298, United States.
authors.forename: Renata
authors.initials: R
authors.lastname: Kolanos
authors.affiliation: †Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, United States.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: De Felice
authors.affiliation: ‡Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia 23298, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000661:Amphetamine / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004298:Dopamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D015259:Dopamine Agents / Q000737:chemistry / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D000661:Amphetamine; D004298:Dopamine
keywords: Human dopamine transporter; Xenopus oocyte expression; amphetamine; deconstruction; dopamine; electrophysiology