The N terminus of monoamine transporters is a lever required for the action of amphetamines.

The Journal of Biological Chemistry
Sonja SucicHarald H Sitte

Abstract

The serotonin transporter (SERT) terminates neurotransmission by removing serotonin from the synaptic cleft. In addition, it is the site of action of antidepressants (which block the transporter) and of amphetamines (which induce substrate efflux). We explored the functional importance of the N terminus in mediating the action of amphetamines by focusing initially on the highly conserved threonine residue at position 81, a candidate site for phosphorylation by protein kinase C. Molecular dynamics simulations of the wild type SERT, compared with its mutations SERT(T81A) and SERT(T81D), suggested structural changes in the inner vestibule indicative of an opening of the inner vestibule. Predictions from this model (e.g. the preferential accumulation of SERT(T81A) in the inward conformation, its reduced turnover number, and a larger distance between its N and C termini) were verified. Most importantly, SERT(T81A) (and the homologous mutations in noradrenaline and dopamine) failed to support amphetamine-induced efflux, and this was not remedied by aspartate at this position. Amphetamine-induced currents through SERT(T81A) were comparable with those through the wild type transporter. Both abundant Na(+) entry and accumulation of SERT...Continue Reading

References

Feb 15, 1991·The Journal of Biological Chemistry·T A Waldmann
Aug 27, 1966·Nature·O Jardetzky
Oct 4, 1993·Biochimica Et Biophysica Acta·G Rudnick, J Clark
Apr 1, 1994·Neuron·S MagerH A Lester
Aug 6, 1996·Proceedings of the National Academy of Sciences of the United States of America·A GalliL J DeFelice
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Sep 15, 1998·Methods : a Companion to Methods in Enzymology·S N Sarkar, G C Sen
May 24, 2000·Proceedings of the National Academy of Sciences of the United States of America·C SaundersA Galli
Aug 31, 2000·Analytical Biochemistry·G H PattersonB G Barisas
Nov 6, 2001·Journal of Biochemical and Biophysical Methods·A Einhauer, A Jungbauer
Nov 16, 2001·Biochemical Society Transactions·J HaaseC Williams
Jan 31, 2002·Proceedings of the National Academy of Sciences of the United States of America·Claus Juul LolandUlrik Gether
Apr 10, 2002·The Journal of Biological Chemistry·Petra ScholzeHarald H Sitte
May 8, 2002·The Journal of Biological Chemistry·James D FosterRoxanne A Vaughan
Dec 14, 2002·Brain Research. Molecular Brain Research·Sonja Sucic, Lesley J Bryan-Lluka
May 15, 2003·The Journal of Biological Chemistry·Tatiana SorkinaAlexander Sorkin
Nov 13, 2003·European Journal of Pharmacology·Margaret E Gnegy
Apr 23, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Nina HansraMichael W Quick
Sep 11, 2004·The Journal of Biological Chemistry·Anne-Kristine MeinildUlrik Gether
Oct 7, 2005·Microscopy Research and Technique·Jérôme N FeigeLaurent Gelman
May 26, 2006·Handbook of Experimental Pharmacology·K Nørgaard-Nielsen, U Gether
May 26, 2006·Handbook of Experimental Pharmacology·K Gerstbrein, H H Sitte
May 26, 2006·Handbook of Experimental Pharmacology·J D FosterR A Vaughan

❮ Previous
Next ❯

Citations

Oct 18, 2012·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Michael H BaumannCharles W Schindler
Jun 17, 2010·The Journal of Biological Chemistry·Jacob EriksenUlrik Gether
Nov 11, 2011·The Journal of Biological Chemistry·Klaus SchickerWalter Sandtner
Oct 29, 2011·The Journal of Biological Chemistry·Linda WildlingPeter Hinterdorfer
Mar 28, 2012·The Journal of Biological Chemistry·Simon BullingWalter Sandtner
Jun 23, 2012·The Journal of Biological Chemistry·James D FosterRoxanne A Vaughan
Nov 20, 2012·The Journal of Biological Chemistry·Amy E MoritzRoxanne A Vaughan
Oct 14, 2011·Molecular Pharmacology·Balasubramaniam AnnamalaiSammanda Ramamoorthy
Oct 1, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Deanna M NavaroliHaley E Melikian
Feb 1, 2011·Expert Opinion on Drug Discovery·Trine KvistHans Bräuner-Osborne
Sep 3, 2013·Expert Opinion on Drug Discovery·Kalyan ImmadisettyJeffry D Madura
Mar 20, 2013·Molecular Aspects of Medicine·Akula Bala PramodL Keith Henry
Nov 4, 2015·Frontiers in Pharmacology·Julie GrouleffBirgit Schiøtt
Nov 21, 2013·British Journal of Pharmacology·Walter SandtnerHarald H Sitte
Apr 8, 2015·Biochimica Et Biophysica Acta·George Khelashvili, Harel Weinstein
Dec 10, 2013·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Peter ChibaThomas Stockner
Jan 28, 2014·Neurochemistry International·Trine Nygaard JørgensenUlrik Gether
Aug 24, 2013·Trends in Pharmacological Sciences·Roxanne A Vaughan, James D Foster
Dec 30, 2014·Trends in Pharmacological Sciences·Harald H Sitte, Michael Freissmuth
Sep 4, 2016·Pharmacological Reviews·Daniel P Bermingham, Randy D Blakely
Jan 20, 2017·Nature Communications·Andreas AnderluhGerhard J Schütz
Feb 14, 2018·The Journal of General Physiology·Peter S HasenhuetlWalter Sandtner
Oct 28, 2015·The Journal of Biological Chemistry·Yang LiWalter Sandtner
Jun 20, 2019·Open Biology·Emmanuel Mikros, George Diallinas
Jul 26, 2013·The Journal of Biological Chemistry·Mattias RickhagUlrik Gether

❮ Previous
Next ❯

Methods Mentioned

BETA
fluorescence resonance
FRET
PCR
transfection
PCA
confocal microscopy
for
transfections
saturation binding

Software Mentioned

DESMOND
MOE
NetPhos
Zeiss LSM Image Browser
Image J PixFRET Plugin
VMD
DESMOND Dynamics System
Image J
Image J PixFRET
Metamorph

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.