Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Original Paper

Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia

Comasco E.a · Vumma R.b · Toffoletto S.a · Johansson J.c · Flyckt L.d · Lewander T.c · Oreland L.a · Bjerkenstedt L.e · Andreou D.d · Söderman E.d · Terenius L.d · Agartz I.d,f,g · Jönsson E.G.d, f · Venizelos N.c

Author affiliations

aDepartment of Neuroscience, Uppsala University, Uppsala, bDepartment of Chemistry and Biomedical Sciences, Faculty of Health and Life Sciences, Linnaeus University, Kalmar, cDepartment of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, dDepartment of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, eStrömstad Academy, Strömstad, Sweden; fNORMENT, K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, and gDepartment of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway

Related Articles for ""

Neuropsychobiology 2016;74:96-103

Do you have an account?

Login Information





Contact Information












By signing up for MyKarger you will automatically participate in our year-End raffle.
If you Then Do Not wish To participate, please uncheck the following box.

Yes, I wish To participate In the year-End raffle And Get the chance To win some Of our most interesting books, And other attractive prizes.


I have read the Karger Terms and Conditions and agree.



Login Information





Contact Information












By signing up for MyKarger you will automatically participate in our year-End raffle.
If you Then Do Not wish To participate, please uncheck the following box.

Yes, I wish To participate In the year-End raffle And Get the chance To win some Of our most interesting books, And other attractive prizes.


I have read the Karger Terms and Conditions and agree.



To view the fulltext, please log in

To view the pdf, please log in

Buy

  • FullText & PDF
  • Unlimited re-access via MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!

If you would like to redeem your KAB credit, please log in.


Save over 20% compared to the individual article price.
Learn more

Rent/Cloud

  • Rent for 48h to view
  • Buy Cloud Access for unlimited viewing via different devices
  • Synchronizing in the ReadCube Cloud
  • Printing and saving restrictions apply

Rental: USD 8.50
Cloud: USD 20.00


Select

Subscribe

  • Access to all articles of the subscribed year(s) guaranteed for 5 years
  • Unlimited re-access via Subscriber Login or MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

Subcription rates


Select

* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: May 29, 2016
Accepted: December 20, 2016
Published online: February 11, 2017
Issue release date: April 2017

Number of Print Pages: 8
Number of Figures: 2
Number of Tables: 2

ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)

For additional information: https://www.karger.com/NPS

Abstract

Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.

© 2017 S. Karger AG, Basel


References

  1. Andreasen NC: The lifetime trajectory of schizophrenia and the concept of neurodevelopment. Dialogues Clin Neurosci 2010;12:409-415.
    External Resources
  2. Babu E, Kanai Y, Chairoungdua A, Kim do K, Iribe Y, Tangtrongsup S, Jutabha P, Li Y, Ahmed N, Sakamoto S, Anzai N, Nagamori S, Endou H: Identification of a novel system l amino acid transporter structurally distinct from heterodimeric amino acid transporters. J Biol Chem 2003;278:43838-43845.
  3. Bodoy S, Martin L, Zorzano A, Palacin M, Estevez R, Bertran J: Identification of LAT4, a novel amino acid transporter with system L activity. J Biol Chem 2005;280:12002-12011.
  4. Vumma R, Wiesel FA, Flyckt L, Bjerkenstedt L, Venizelos N: Functional characterization of tyrosine transport in fibroblast cells from healthy controls. Neurosci Lett 2008;434:56-60.
  5. Flyckt L, Venizelos N, Edman G, Bjerkenstedt L, Hagenfeldt L, Wiesel FA: Aberrant tyrosine transport across the cell membrane in patients with schizophrenia. Arch Gen Psychiatry 2001;58:953-958.
  6. Ramchand CN, Peet M, Clark AE, Gliddon AE, Hemmings GP: Decreased tyrosine transport in fibroblasts from schizophrenics: implications for membrane pathology. Prostaglandins Leukot Essent Fatty Acids 1996;55:59-64.
  7. Hagenfeldt L, Venizelos N, Bjerkenstedt L, Wiesel FA: Decreased tyrosine transport in fibroblasts from schizophrenic patients. Life Sci 1987;41:2749-2757.
  8. Wiesel FA, Venizelos N, Bjerkenstedt L, Hagenfeldt L: Tyrosine transport in schizophrenia. Schizophr Res 1994;13:255-258.
  9. Montgomery AJ, McTavish SF, Cowen PJ, Grasby PM: Reduction of brain dopamine concentration with dietary tyrosine plus phenylalanine depletion: an [11C]raclopride PET study. Am J Psychiatry 2003;160:1887-1889.
  10. Harmer CJ, McTavish SF, Clark L, Goodwin GM, Cowen PJ: Tyrosine depletion attenuates dopamine function in healthy volunteers. Psychopharmacology (Berl) 2001;154:105-111.
  11. Wiesel FA, Edman G, Flyckt L, Eriksson A, Nyman H, Venizelos N, Bjerkenstedt L: Kinetics of tyrosine transport and cognitive functioning in schizophrenia. Schizophr Res 2005;74:81-89.
  12. Wiesel FA, Blomqvist G, Halldin C, Sjogren I, Bjerkenstedt L, Venizelos N, Hagenfeldt L: The transport of tyrosine into the human brain as determined with l-[1-11C]tyrosine and PET. J Nucl Med 1991;32:2043-2049.
    External Resources
  13. Wiesel FA, Andersson JL, Westerberg G, Wieselgren IM, Bjerkenstedt L, Hagenfeldt L, Langstrom B: Tyrosine transport is regulated differently in patients with schizophrenia. Schizophr Res 1999;40:37-42.
  14. Tamminga CA, Medoff DR: The biology of schizophrenia. Dialogues Clin Neurosci 2000;2:339-348.
    External Resources
  15. Lichtenstein P, Yip BH, Bjork C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM: Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009;373:234-239.
  16. Schizophrenia Working Group of the Psychiatric Genomics C: Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421-427.
  17. Jönsson EG, Edman-Ahlbom B, Sillén A, Gunnar A, Kulle B, Frigessi A, Vares M, Ekholm B, Wode-Helgodt B, Schumacher J, Cichon S, Agartz I, Sedvall GC, Hall H, Terenius L: Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:924-933.
  18. Ekholm B, Ekholm A, Adolfsson R, Vares M, Ösby U, Sedvall GC, Jönsson EG: Evaluation of diagnostic procedures in Swedish patients with schizophrenia and related psychoses. Nord J Psychiatry 2005;59:457-464.
  19. Vares M, Ekholm A, Sedvall GC, Hall H, Jönsson EG: Characterisation of patients with schizophrenia and related psychosis: evaluation of different diagnostic procedures. Psychopathology 2006;39:286-295.
  20. Andreou D, Söderman E, Axelsson T, Sedvall GC, Terenius L, Agartz I, Jönsson EG: Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis. Behav Brain Funct 2014;10:26.
  21. Andreou D, Söderman E, Axelsson T, Sedvall GC, Terenius L, Agartz I, Jönsson EG: Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis. Psychiatry Res 2015;229:497-504.
  22. Jönsson EG, Saetre P, Edman-Ahlbom B, Sillen A, Gunnar A, Andreou D, Agartz I, Sedvall G, Hall H, Terenius L: Brain-derived neurotrophic factor gene variation influences cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol concentrations in healthy volunteers. J Neural Transm 2008;115:1695-1699.
  23. Geijer T, Neiman J, Rydberg U, Gyllander A, Jönsson E, Sedvall G, Valverius P, Terenius L: Dopamine D2 receptor gene polymorphisms in Scandinavian chronic alcoholics. Eur Arch Psychiatry Clin Neurosci 1994;244:26-32.
  24. Steemers FJ, Chang W, Lee G, Barker DL, Shen R, Gunderson KL: Whole-genome genotyping with the single-base extension assay. Nat Methods 2006;3:31-33.
  25. Gunderson KL, Steemers FJ, Lee G, Mendoza LG, Chee MS: A genome-wide scalable SNP genotyping assay using microarray technology. Nat Genet 2005;37:549-554.
  26. Hatanaka T, Huang W, Martindale RG, Ganapathy V: Differential influence of cAMP on the expression of the three subtypes (ATA1, ATA2, and ATA3) of the amino acid transport system A. FEBS Lett 2001;505:317-320.
  27. Killian DM, Chikhale PJ: Predominant functional activity of the large, neutral amino acid transporter (LAT1) isoform at the cerebrovasculature. Neurosci Lett 2001;306:1-4.
  28. Olsson E, Wiesel FA, Bjerkenstedt L, Venizelos N: Tyrosine transport in fibroblasts from healthy volunteers and patients with schizophrenia. Neurosci Lett 2006;393:211-215.
  29. Broer S, Broer A, Hansen JT, Bubb WA, Balcar VJ, Nasrallah FA, Garner B, Rae C: Alanine metabolism, transport, and cycling in the brain. J Neurochem 2007;102:1758-1770.
  30. Ackenheil M: Neurotransmitters and signal transduction processes in bipolar affective disorders: a synopsis. J Affect Disord 2001;62:101-111.
  31. Carlsson A, Hansson LO, Waters N, Carlsson ML: Neurotransmitter aberrations in schizophrenia: new perspectives and therapeutic implications. Life Sci 1997;61:75-94.
  32. Wise RA, Bozarth MA: A psychomotor stimulant theory of addiction. Psychol Rev 1987;94:469-492.
    External Resources
  33. Persson ML, Johansson J, Vumma R, Raita J, Bjerkenstedt L, Wiesel FA, Venizelos N: Aberrant amino acid transport in fibroblasts from patients with bipolar disorder. Neurosci Lett 2009;457:49-52.
  34. Lee AG: Ca2+-ATPase structure in the E1 and E2 conformations: mechanism, helix-helix and helix-lipid interactions. Biochim Biophys Acta 2002;1565:246-266.
  35. Feneant-Thibault M, Galera P, Maccario J, Boutron A, Pujol JP, Moatti N: Interleukin-1 beta-induced changes in the kinetic constants of l-proline uptake in human skin fibroblasts. Biochem J 1991;276:57-62.
  36. Fernell E, Karagiannakis A, Edman G, Bjerkenstedt L, Wiesel FA, Venizelos N: Aberrant amino acid transport in fibroblasts from children with autism. Neurosci Lett 2007;418:82-86.
  37. Horrobin DF: The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 1998;30:193-208.
  38. McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, et al: Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009;41:1223-1227.
  39. Bachmann-Gagescu R, Mefford HC, Cowan C, Glew GM, Hing AV, Wallace S, Bader PI, Hamati A, Reitnauer PJ, Smith R, Stockton DW, Muhle H, Helbig I, Eichler EE, Ballif BC, Rosenfeld J, Tsuchiya KD: Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med 2010;12:641-647.
  40. Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Ripke S, Wray NR, Lewis CM, Hamilton SP, Weissman MM, Breen G, Byrne EM, Blackwood DH, Boomsma DI, Cichon S, Heath AC, Holsboer F, Lucae S, Madden PA, Martin NG, McGuffin P, Muglia P, Noethen MM, Penninx BP, et al: A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 2013;18:497-511.
  41. Boado RJ, Li JY, Pardridge WM: Site-directed mutagenesis of rabbit LAT1 at amino acids 219 and 234. J Neurochem 2003;84:1322-1331.
  42. Boado RJ, Li JY, Wise P, Pardridge WM: Human LAT1 single nucleotide polymorphism N230K does not alter phenylalanine transport. Mol Genet Metab 2004;83:306-311.
  43. Bik-Multanowski M, Pietrzyk JJ: LAT1 gene variants - potential factors influencing the clinical course of phenylketonuria. J Inherit Metab Dis 2006;29:684.

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: May 29, 2016
Accepted: December 20, 2016
Published online: February 11, 2017
Issue release date: April 2017

Number of Print Pages: 8
Number of Figures: 2
Number of Tables: 2

ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)

For additional information: https://www.karger.com/NPS


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.