Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase

Proceedings of the National Academy of Sciences of the United States of America
Harish C PrasadRandy D Blakely

Abstract

Human serotonin [5-hydroxytryptamine (5-HT)] transporters (hSERT, 5HTT, and SLC6A4) inactivate 5-HT after release and are prominent targets for therapeutic intervention in mood, anxiety, and obsessive-compulsive disorders. Multiple hSERT coding variants have been identified, although to date no comprehensive functional analysis of these variants has been reported. We transfected hSERT or 10 hSERT coding variants and examined total and surface protein expression, antagonist recognition, and transporter modulation by posttranslational, regulatory pathways. Two variants, Pro339Leu and Ile425Val, demonstrated significant changes in surface expression supporting alterations in 5-HT transport capacity (V(max)). Regardless of basal transport activity, all SERT variants displayed a capacity for rapid, phorbol ester-triggered down-regulation. Remarkably, five variants (Thr4Ala, Gly56Ala, Glu215Lys, Lys605Asn, and Pro612Ser) demonstrated no capacity for 5-HT uptake stimulation after acute protein kinase G (PKG)/p38 mitogen-activated protein kinase (MAPK) activation. Epstein-Barr virus (EBV)-transformed lymphocytes natively expressing the most common of these variants (Gly56Ala) exhibited a similar loss of 5-HT uptake stimulation by PKG/p...Continue Reading

References

Apr 20, 2010·Psychopharmacology·Michael R Bruchas, Charles Chavkin
Feb 3, 2009·Neurogenetics·B M AndersonJ L Haines
Jul 30, 2011·Biochemistry·Jonathan J Sager, Gonzalo E Torres
Jan 22, 2013·ACS Chemical Neuroscience·Brendan S BeikmannAnne Milasincic Andrews
Jan 22, 2013·ACS Chemical Neuroscience·Nicole Baganz, Randy D Blakely
Dec 14, 2011·Molecular Psychiatry·S L DiazL Maroteaux
Mar 1, 2012·Nature Neuroscience·Evan S Deneris, Steven C Wyler
Sep 23, 2011·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Jeremy Veenstra-Vanderweele, Randy D Blakely
Jan 23, 2008·Nature Reviews. Neuroscience·Dennis L Murphy, Klaus-Peter Lesch
Feb 3, 2006·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Chong-Bin ZhuWilliam A Hewlett
Mar 22, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Jens R WendlandDennis L Murphy
Apr 5, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Sarah CrossJeremy Veenstra-Vanderweele
Sep 21, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Matthäus WilleitErnst A Singer
Oct 30, 2009·Proceedings of the National Academy of Sciences of the United States of America·Benjamin B LandCharles Chavkin
Feb 2, 2011·Proceedings of the National Academy of Sciences of the United States of America·Brent J ThompsonRandy D Blakely
Mar 21, 2012·Proceedings of the National Academy of Sciences of the United States of America·Jeremy Veenstra-VanderweeleRandy D Blakely
Nov 26, 2010·The Journal of Biological Chemistry·Yuan-Wei Zhang, Gary Rudnick
Nov 14, 2008·Psychosomatic Medicine·Barbara Phillips-ButePerioperative Genetics and Safety Outcomes Investigative Team
Jan 17, 2008·Psychiatric Genetics·Jens R WendlandDennis L Murphy
Oct 30, 2008·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Harish C PrasadRandy D Blakely
Dec 27, 2011·Cold Spring Harbor Perspectives in Biology·Randy D Blakely, Robert H Edwards
Oct 14, 2011·Molecular Pharmacology·Balasubramaniam AnnamalaiSammanda Ramamoorthy
Oct 28, 2006·Annual Review of Pharmacology and Toxicology·Maureen K Hahn, Randy D Blakely
Oct 3, 2013·Molecular Autism·Travis M KerrJeremy Veenstra-Vanderweele
Dec 16, 2005·The AAPS Journal·Lankupalle D Jayanthi, Sammanda Ramamoorthy
Jun 30, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jerry C ChangSandra J Rosenthal
Oct 26, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Michael R BruchasCharles Chavkin
Jan 15, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Christi J WylieEvan S Deneris
Jan 24, 2014·ACS Chemical Biology·Lena SørensenAnders S Kristensen
Sep 28, 2014·Progress in Neuro-psychopharmacology & Biological Psychiatry·Preeti JaiswalUsha Rajamma
May 28, 2005·Archives of Pharmacal Research·Soon-Youl LeeUhtaek Oh
Dec 31, 2009·Neurochemical Research·Gino GiannacciniAntonio Lucacchini
May 25, 2012·Journal of Psychiatric Research·Beatriz CamarenaAlejandro Caballero
May 18, 2010·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Karen L JonesDavid Q Beversdorf
Oct 20, 2009·Neurochemistry International·Tamara KuchmerovskaArkady Klimenko

Citations

Jan 1, 1992·Physiological Reviews·B L Jacobs, E C Azmitia
Oct 25, 1991·Science·B J HoffmanM J Brownstein
Mar 1, 1991·Journal of Autism and Developmental Disorders·J PivenS E Folstein
Jan 1, 1990·Annals of the New York Academy of Sciences·H Y Meltzer
Jan 1, 1990·Annals of the New York Academy of Sciences·T R InselD L Murphy
Jul 15, 1982·The New England Journal of Medicine·R D Ciaranello
Mar 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·Sammanda RamamoorthyRandy D Blakely
Aug 1, 1996·Current Opinion in Pediatrics·E H Cook, B L Leventhal
Nov 5, 1997·Journal of Neurochemistry·C C Bradley, Randy D Blakely
Jan 27, 1998·The Journal of Biological Chemistry·Sammanda RamamoorthyRandy D Blakely
Jun 20, 1998·The Journal of Biological Chemistry·J G ChenGary Rudnick
Nov 24, 1998·The Journal of Comparative Neurology·C LebrandP Gaspar
Jan 20, 1999·Alimentary Pharmacology & Therapeutics·F M WardR V Heatley
Feb 24, 2000·The New England Journal of Medicine·J R ShannonD Robertson
Jun 19, 2001·American Journal of Human Genetics·J K Pritchard
Aug 2, 2001·American Journal of Human Genetics·International Molecular Genetic Study of Autism Consortium (IMGSAC)
Aug 30, 2001·Proceedings of the National Academy of Sciences of the United States of America·H HastrupJ A Javitch
Nov 16, 2001·Biochemical Society Transactions·J HaaseC Williams
Apr 30, 2003·Proceedings of the National Academy of Sciences of the United States of America·Yan ShuPharmacogenetics Of Membrane Transporters Investigators
Jul 19, 2003·Molecular Pharmacology·Fusun KilicGary Rudnick
Sep 19, 2003·American Journal of Human Genetics·Amanda L YonanT Conrad Gilliam
Apr 17, 2004·Molecular Interventions·Dennis L MurphyKlaus-Peter Lesch
Apr 27, 2004·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·J L McCauleyJ S Sutcliffe
Aug 7, 2004·Science·Jonathan C CohenHelen H Hobbs
Oct 7, 2004·American Journal of Human Genetics·Jennifer L StoneStanley F Nelson
Oct 27, 2004·Pharmacology & Therapeutics·Haley E Melikian
Oct 28, 2004·European Journal of Pharmacology·Chong-Bin ZhuRandy D Blakely
Jan 7, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Devadoss J SamuvelSammanda Ramamoorthy
Mar 19, 2005·Molecular Pharmacology·Lankupalle D JayanthiSammanda Ramamoorthy
Jul 22, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Hae-Chul ParkBruce Appel

Related Concepts

Biochemical Pathway
Transfection
Mitogen-Activated Protein Kinases
Lymphocytes as Percentage of Blood Leukocytes (Lab Test)
Serotonin Measurement
Mitogen-Activated Protein Kinase 14
Serotonin
Antagonist Muscle Action
8-bromocyclic GMP
Lymphoid Cells

Related Feeds

Anxiety Disorders

Discover the latest research on anxiety disorders including agoraphobia, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder here.