PMID- 24251585
OWN - NLM
STAT- MEDLINE
DCOM- 20141014
LR  - 20211021
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 171
IP  - 4
DP  - 2014 Feb
TI  - A quantitative model of amphetamine action on the 5-HT transporter.
PG  - 1007-18
LID - 10.1111/bph.12520 [doi]
AB  - BACKGROUND AND PURPOSE: Amphetamines bind to the plasmalemmal transporters for 
      the monoamines dopamine (DAT), noradrenaline (NET) and 5-HT (SERT); influx of 
      amphetamine leads to efflux of substrates. Various models have been proposed to 
      account for this amphetamine-induced reverse transport in mechanistic terms. A 
      most notable example is the molecular stent hypothesis, which posits a special 
      amphetamine-induced conformation that is not likely in alternative access models 
      of transport. The current study was designed to evaluate the explanatory power of 
      these models and the molecular stent hypothesis. EXPERIMENTAL APPROACH: Xenopus 
      laevis oocytes and HEK293 cells expressing human (h) SERT were voltage-clamped 
      and exposed to 5-HT, p-chloroamphetamine (pCA) or methylenedioxyamphetamine 
      (MDMA). KEY RESULTS: In contrast to the currents induced by 5-HT, pCA-triggered 
      currents through SERT decayed slowly in Xenopus laevis oocytes once the agonist 
      was removed (consistent with the molecular stent hypothesis). However, when SERT 
      was expressed in HEK293 cells, currents induced by 3 or 100 muM pCA decayed 10 or 
      100 times faster, respectively, after pCA removal. CONCLUSIONS AND IMPLICATIONS: 
      This discrepancy in decay rates is inconsistent with the molecular stent 
      hypothesis. In contrast, a multistate version of the alternative access model 
      accounts for all the observations and reproduces the kinetic parameters extracted 
      from the electrophysiological recordings. A crucial feature that explains the 
      action of amphetamines is their lipophilic nature, which allows for rapid 
      diffusion through the membrane.
CI  - (c) 2013 The Authors. British Journal of Pharmacology published by John Wiley &. 
      Sons Ltd on behalf of The British Pharmacological Society.
FAU - Sandtner, Walter
AU  - Sandtner W
AD  - Center of Physiology and Pharmacology, Medical University Vienna, Vienna, 
      Austria.
FAU - Schmid, Diethart
AU  - Schmid D
FAU - Schicker, Klaus
AU  - Schicker K
FAU - Gerstbrein, Klaus
AU  - Gerstbrein K
FAU - Koenig, Xaver
AU  - Koenig X
FAU - Mayer, Felix P
AU  - Mayer FP
FAU - Boehm, Stefan
AU  - Boehm S
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  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Serotonin Agents)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 333DO1RDJY (Serotonin)
RN  - 64-12-0 (p-Chloroamphetamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
CIN - Br J Pharmacol. 2015 Oct;172(19):4775-8. PMID: 24824446
CIN - Br J Pharmacol. 2015 Oct;172(19):4772-4. PMID: 24824549
MH  - Animals
MH  - HEK293 Cells
MH  - Humans
MH  - *Models, Biological
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology
MH  - Oocytes/drug effects/physiology
MH  - Serotonin/*pharmacology
MH  - Serotonin Agents/*pharmacology
MH  - Serotonin Plasma Membrane Transport Proteins/*physiology
MH  - Xenopus laevis
MH  - p-Chloroamphetamine/*pharmacology
PMC - PMC3925039
OTO - NOTNLM
OT  - SERT
OT  - amphetamine
OT  - currents
OT  - diffusion
EDAT- 2013/11/21 06:00
MHDA- 2014/10/15 06:00
PMCR- 2015/02/01
CRDT- 2013/11/21 06:00
PHST- 2013/07/04 00:00 [received]
PHST- 2013/10/30 00:00 [revised]
PHST- 2013/11/05 00:00 [accepted]
PHST- 2013/11/21 06:00 [entrez]
PHST- 2013/11/21 06:00 [pubmed]
PHST- 2014/10/15 06:00 [medline]
PHST- 2015/02/01 00:00 [pmc-release]
AID - 10.1111/bph.12520 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2014 Feb;171(4):1007-18. doi: 10.1111/bph.12520.