PMID- 15615700
OWN - NLM
STAT- MEDLINE
DCOM- 20050328
LR  - 20131121
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 67
IP  - 1
DP  - 2005 Jan
TI  - Amphetamines take two to tango: an oligomer-based counter-transport model of 
      neurotransmitter transport explores the amphetamine action.
PG  - 140-51
AB  - Amphetamine congeners [e.g., 3,4-methylenedioxymetamphetamine (MDMA), or 
      "ecstasy"] are substrates for monoamine transporters (i.e., the transporters for 
      serotonin, norepinephrine, and dopamine); however, their in vivo-action relies on 
      their ability to promote monoamine efflux. The mechanistic basis for this counter 
      transport remains enigmatic. We tested the hypothesis that outward transport is 
      contingent on the oligomeric nature of neurotransmitter transporters by creating 
      a concatemer of the serotonin transporter and the amphetamine-resistant GABA 
      transporter. In cells expressing the concatemer, amphetamine analogs promoted 
      GABA efflux and blunted GABA influx. In contrast, the natural substrates 
      serotonin and GABA only cause mutual inhibition of influx via the other 
      transporter moiety in the concatemer. GABA efflux through the concatemer that was 
      promoted by amphetamine analogs was blocked by the protein kinase C inhibitors 
      GF109203X (bisindoylmaleimide I) and Go6983 
      (2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl)maleimide). 
      Thus, based on our observations, we propose that, in the presence of amphetamine 
      analogs, monoamine transporters operate as counter-transporters; influx and 
      efflux occur through separate but coupled moieties. Influx and efflux are coupled 
      via changes in the ionic gradients, but these do not suffice to account for the 
      action of amphetamines; the activity of a protein kinase C isoform provides a 
      second stimulus that primes the inward facing conformation for outward transport.
FAU - Seidel, Stefan
AU  - Seidel S
AD  - Institute of Pharmacology, Medical University Vienna, Wahringer Strasse 13a, 
      A-1090 Vienna, Austria. michael.freissmuth@meduniwien.ac.at
FAU - Singer, Ernst A
AU  - Singer EA
FAU - Just, Herwig
AU  - Just H
FAU - Farhan, Hesso
AU  - Farhan H
FAU - Scholze, Petra
AU  - Scholze P
FAU - Kudlacek, Oliver
AU  - Kudlacek O
FAU - Holy, Marion
AU  - Holy M
FAU - Koppatz, Karl
AU  - Koppatz K
FAU - Krivanek, Peter
AU  - Krivanek P
FAU - Freissmuth, Michael
AU  - Freissmuth M
FAU - Sitte, Harald H
AU  - Sitte HH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Neurotransmitter Agents)
RN  - CK833KGX7E (Amphetamine)
SB  - IM
MH  - Amphetamine/*pharmacokinetics
MH  - Biological Transport/*drug effects
MH  - Cell Line
MH  - Humans
MH  - Kidney
MH  - Kinetics
MH  - Models, Biological
MH  - Neurotransmitter Agents/*pharmacokinetics
EDAT- 2004/12/24 09:00
MHDA- 2005/03/29 09:00
CRDT- 2004/12/24 09:00
PHST- 2004/12/24 09:00 [pubmed]
PHST- 2005/03/29 09:00 [medline]
PHST- 2004/12/24 09:00 [entrez]
AID - 67/1/140 [pii]
AID - 10.1124/mol.67.1. [doi]
PST - ppublish
SO  - Mol Pharmacol. 2005 Jan;67(1):140-51. doi: 10.1124/mol.67.1..