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Haley E Melikian PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentNeurobiology
AddressUniversity of Massachusetts Medical School
303 Belmont Street
Worcester MA 01605
Phone508-856-4045
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentBiochemistry and Molecular Pharmacology

    InstitutionUMMS - School of Medicine
    DepartmentNeurobiology

    InstitutionUMMS - School of Medicine
    DepartmentNeuroNexus Neuroscience Institute

    InstitutionUMMS - School of Medicine
    DepartmentPsychiatry
    DivisionBrudnick Neuropsychiatric Research Institute

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentBiochemistry and Molecular Pharmacology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentNeuroscience

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentTranslational Science

    InstitutionUMMS - Programs, Centers and Institutes
    DepartmentBrudnick Neuropsychiatric Research Institute


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    Collapse Biography 
    Collapse education and training
    University of Massachusetts Amherst, Amherst, MA, United StatesBSBiochemistry
    Emory University, Atlanta, GA, United StatesPHDNeuroscience
    Howard Hughes Medical Institute, Emory University, Atlanta, GAPostdoctoral07/1997Genetics/Neurobiology
    Harvard Medical School, Boston, MAPostdoctoral12/2000Neurobiology

    Collapse Overview 
    Collapse overview

    Monoamine Transporters, Neuropsychiatric Disorders and Addiction


    Our laboratory is interested in the molecular mechanisms that regulate presynaptic dopamine reuptake by the dopamine (DA) transporter (DAT).  DA neurotransmission is required for executive function, working memory, reward and movement, and DA dysfunction is associated with several neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), schizophrenia, addiction and Parkinson’s disease.  Extracellular DA is temporally and spatially restricted by presynaptic DA reuptake facilitated by the DAT. In addition to its central role in basal synaptic transmission, DAT is the primary target for addictive psychostimulants, cocaine and amphetamine, as well as therapeutic psychoactive drugs, such as methylphenidate (Ritalin) and bupropion (Wellbutrin/Zyban).  These agents block DAT activity and thereby enhance extracellular DA levels and DA-related behaviors. 


    Given DAT’s importance in DAergic neurotransmission and as a psychoactive drug target, cellular mechanisms that impact DAT function are likely to have significant impact on DA signaling and neuropsychiatric disorders.  Multiple DAT coding variants have been identified in ADHD and autism patients, further supporting that altered DAT function is linked to significant behavioral consequences.  Work from our lab investigates the cellular and molecular mechanisms that regulate DAT.  Endocytic trafficking dynamically controls DAT plasma membrane availability, and a variety of cellular signaling pathways and psychostimulant drugs rapid alter DAT trafficking, surface expression and function. We have identified multiple key players that govern DAT trafficking.  Using a variety of cutting edge approaches, such as viral-mediated gene expression, gene silencing (RNAi), optogenetics and chemogenetics, we are investigating how DAT regulation impacts DA neurotransmission and DA-associated behaviors.



    Collapse Rotation Projects

    Potential Rotation Projects

    1.  Mechanisms Controlling Amphetamine-Stimulated Dopamine Transporter Trafficking:  Amphetamine exposure causes a rapid loss of dopamine transporter from the plasma membrane, compromising synaptic dopamine removal.  However, the endocytic mechanisms responsible for amphetamine-mediated dopamine transporter internalization are not well understood.  This project will use state-of-the-art cellular imaging and molecular approaches to investigate these mechanisms.  Students will receive training in cellular, molecular and biochemical approaches to understanding neuronal membrane protein trafficking and regulation.

    2. Role of Dopamine Transporter Trafficking in Psychostimulant Addiction:  This project is to determine whether membrane trafficking of the dopamine transporter is required for cocaine and amphetamine addiction.  Students will use RNAi technology to knockdown in vivo proteins required for dopamine transporter trafficking, and subsequently perform biochemical and behavioral studies to assess both transporter trafficking and addictive behaviors, respectively.  This project will train students in cellular, molecular, biochemical and behavioral approaches to studying addiction.

    3. Differential structure/function analysis of biogenic amine transporter trafficking and regulation:  Although all biogenic amine transporters downregulate and internalize in response to PKC activation, recent studies demonstrate that the molecular mechanisms mediating these processes are distinct.  This project will identify dopamine transporter target sequences/domains that confer mechanistic specificity for constitutive and regulated trafficking.  Students will gain expertise in cellular and molecular approaches to understanding membrane trafficking mechanisms.


    Collapse Post Docs

    I am seeking an accomplished and motivated Ph.D. electrophysiologist to study the impact of dopamine transporter trafficking and regulation on dopaminergic neurotransmission. This is an exciting opportunity to integrate state-of-art optogenetic, chemogenetic and transgenic mouse approaches to link molecular mechanisms to synaptic physiology. Candidates will have a strong track record of productivity from their doctoral research, with excellent verbal and written skills, with expertise in ex vivo brain slice electrophysiological approaches. Interested candidates should forward a cover letter, curriculum vitae, and the names and contact information of three references via e-mail to:  


    Haley E. Melikian, Ph.D.


    Brudnick Neuropsychiatric Research Institute


    UMASS Medical School


    haley.melikian@umassmed.edu





    Collapse Research 
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    R01DA015169     (MELIKIAN, HALEY E)May 1, 2002 - Aug 31, 2018
    NIH
    Trafficking and Regulation of Monoamine Transporters
    Role: Principal Investigator

    R01DA035224     (MELIKIAN, HALEY E)May 1, 2013 - Jan 31, 2018
    NIH
    Dopamine Transporter Cell Surface Dynamics
    Role: Principal Investigator

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Wu S, Fagan RR, Uttamapinant C, Lifshitz LM, Fogarty KE, Ting AY, Melikian HE. The Dopamine Transporter Recycles Via A Retromer-Dependent Post-Endocytic Mechanism: Tracking Studies Using A Novel Fluorophore-Coupling Approach. J Neurosci. 2017 Aug 28. PMID: 28847807.
      View in: PubMed
    2. Sweeney CG, Tremblay BP, Stockner T, Sitte HH, Melikian HE. Dopamine Transporter Amino- and Carboxy-Termini Synergistically Contribute to Substrate and Inhibitor Affinities. J Biol Chem. 2016 Dec 16. PMID: 27986813.
      View in: PubMed
    3. Wu S, Bellve KD, Fogarty KE, Melikian HE. Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant. Proc Natl Acad Sci U S A. 2015 Dec 15; 112(50):15480-5. PMID: 26621748.
      View in: PubMed
    4. Gabriel LR, Wu S, Melikian HE. Brain slice biotinylation: an ex vivo approach to measure region-specific plasma membrane protein trafficking in adult neurons. J Vis Exp. 2014 Apr 03; (86). PMID: 24747337.
      View in: PubMed
    5. Gabriel LR, Wu S, Kearney P, Bellvé KD, Standley C, Fogarty KE, Melikian HE. Dopamine transporter endocytic trafficking in striatal dopaminergic neurons: differential dependence on dynamin and the actin cytoskeleton. J Neurosci. 2013 Nov 6; 33(45):17836-46. PMID: 24198373.
      View in: PubMed
    6. Gabriel L, Lvov A, Orthodoxou D, Rittenhouse AR, Kobertz WR, Melikian HE. The acid-sensitive, anesthetic-activated potassium leak channel, KCNK3, is regulated by 14-3-3ß-dependent, protein kinase C (PKC)-mediated endocytic trafficking. J Biol Chem. 2012 Sep 21; 287(39):32354-66. PMID: 22846993.
      View in: PubMed
    7. Navaroli DM, Stevens ZH, Uzelac Z, Gabriel L, King MJ, Lifshitz LM, Sitte HH, Melikian HE. The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking. J Neurosci. 2011 Sep 28; 31(39):13758-70. PMID: 21957239.
      View in: PubMed
    8. Navaroli DM, Melikian HE. Insertion of tetracysteine motifs into dopamine transporter extracellular domains. PLoS One. 2010 Feb 09; 5(2):e9113. PMID: 20161733.
      View in: PubMed
    9. Gabriel L, Stevens Z, Melikian H. Measuring plasma membrane protein endocytic rates by reversible biotinylation. J Vis Exp. 2009 Dec 23; (34). PMID: 20032927.
      View in: PubMed
    10. Boudanova E, Navaroli DM, Stevens Z, Melikian HE. Dopamine transporter endocytic determinants: carboxy terminal residues critical for basal and PKC-stimulated internalization. Mol Cell Neurosci. 2008 Oct; 39(2):211-7. PMID: 18638559.
      View in: PubMed
    11. Boudanova E, Navaroli DM, Melikian HE. Amphetamine-induced decreases in dopamine transporter surface expression are protein kinase C-independent. Neuropharmacology. 2008 Mar; 54(3):605-12. PMID: 18164041.
      View in: PubMed
    12. Holton KL, Loder MK, Melikian HE. Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization. Nat Neurosci. 2005 Jul; 8(7):881-8. PMID: 15924135.
      View in: PubMed
    13. Melikian HE. Neurotransmitter transporter trafficking: endocytosis, recycling, and regulation. Pharmacol Ther. 2004 Oct; 104(1):17-27. PMID: 15500906.
      View in: PubMed
    14. Loder MK, Melikian HE. The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines. J Biol Chem. 2003 Jun 13; 278(24):22168-74. PMID: 12682063.
      View in: PubMed
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