Top

Published in:

Open Access 01-12-2015 | Letter to the Editor

Zn²⁺ reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder

Authors: Peter J Hamilton, Aparna Shekar, Andrea N Belovich, Nicole Bibus Christianson, Nicholas G Campbell, James S Sutcliffe, Aurelio Galli, Heinrich JG Matthies, Kevin Erreger

Published in: Molecular Autism | Issue 1/2015

Abstract

Our laboratory recently characterized a novel autism spectrum disorder (ASD)-associated de novo missense mutation in the human dopamine transporter (hDAT) gene SLC6A3 (hDAT T356M). This hDAT variant exhibits dysfunctional forward and reverse transport properties that may contribute to DA dysfunction in ASD. Here, we report that Zn²⁺ reverses, at least in part, the functional deficits of ASD-associated hDAT variant T356M. These data suggest that the molecular mechanism targeted by Zn²⁺ to restore partial function in hDAT T356M may be a novel therapeutic target to rescue functional deficits in hDAT variants associated with ASD.

Kristensen AS, Andersen J, Jorgensen TN, Sorensen L, Eriksen J, Loland CJ, et al. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev. 2011;63(3):585–640. doi:10.1124/pr.108.000869.CrossRefPubMed

Norregaard L, Frederiksen D, Nielsen EO, Gether U. Delineation of an endogenous zinc-binding site in the human dopamine transporter. EMBO J. 1998;17(15):4266–73.CrossRefPubMedCentralPubMed

Loland CJ, Norregaard L, Gether U. Defining proximity relationships in the tertiary structure of the dopamine transporter. Identification of a conserved glutamic acid as a third coordinate in the endogenous Zn(2+)-binding site. J Biol Chem. 1999;274(52):36928–34.CrossRefPubMed

Krishnamurthy H, Gouaux E. X-ray structures of LeuT in substrate-free outward-open and apo inward-open states. Nature. 2012;481(7382):469–74. doi:10.1038/nature10737.CrossRefPubMedCentralPubMed

Hamilton PJ, Campbell NG, Sharma S, Erreger K, Herborg Hansen F, Saunders C, et al. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. Mol Psychiatry. 2013;18(12):1315–23. doi:10.1038/mp.2013.102.CrossRefPubMedCentralPubMed

Sulzer D, Sonders MS, Poulsen NW, Galli A. Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol. 2005;75(6):406–33.CrossRefPubMed

Kahlig KM, Lute BJ, Wei Y, Loland CJ, Gether U, Javitch JA, et al. Regulation of dopamine transporter trafficking by intracellular amphetamine. Mol Pharmacol. 2006;70(2):542–8. doi:10.1124/mol.106.023952.CrossRefPubMed

Loland CJ, Norregaard L, Litman T, Gether U. Generation of an activating Zn(2+) switch in the dopamine transporter: mutation of an intracellular tyrosine constitutively alters the conformational equilibrium of the transport cycle. Proc Natl Acad Sci U S A. 2002;99(3):1683–8.CrossRefPubMedCentralPubMed

Stockner T, Montgomery TR, Kudlacek O, Weissensteiner R, Ecker GF, Freissmuth M, et al. Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model. PLoS Comput Biol. 2013;9(2):e1002909. doi:10.1371/journal.pcbi.1002909.CrossRefPubMedCentralPubMed

10.

Faber S, Zinn GM, Kern 2nd JC, Kingston HM. The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Biomarkers. 2009;14(3):171–80. doi:10.1080/13547500902783747.CrossRefPubMed

11.

Jackson MJ, Garrod PJ. Plasma zinc, copper, and amino acid levels in the blood of autistic children. J Autism Child Schizophr. 1978;8(2):203–8.CrossRefPubMed

12.

Li SO, Wang JL, Bjorklund G, Zhao WN, Yin CH. Serum copper and zinc levels in individuals with autism spectrum disorders. Neuroreport. 2014;25(15):1216–20. doi:10.1097/WNR.0000000000000251.CrossRefPubMed

Title: Zn2+ reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder
Authors: Peter J Hamilton
Aparna Shekar
Andrea N Belovich
Nicole Bibus Christianson
Nicholas G Campbell
James S Sutcliffe
Aurelio Galli
Heinrich JG Matthies
Kevin Erreger
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Molecular Autism / Issue 1/2015
Electronic ISSN: 2040-2392
DOI: https://doi.org/10.1186/s13229-015-0002-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Zn²⁺ reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2015

Sex-different abnormalities in the right second to fourth digit ratio in Japanese individuals with autism spectrum disorders

Social communication and emotion difficulties and second to fourth digit ratio in a large community-based sample

Hypomethylation of miR-142 promoter and upregulation of microRNAs that target the oxytocin receptor gene in the autism prefrontal cortex

Auditory encoding abnormalities in children with autism spectrum disorder suggest delayed development of auditory cortex

Atypical integration of social cues for orienting to gaze direction in adults with autism

Sex differences in structural organization of motor systems and their dissociable links with repetitive/restricted behaviors in children with autism