Jonathan A. Javitch, MD, PhD

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Overview

Academic Appointments

  • Lieber Professor of Experimental Therapeutics (in Psychiatry)
  • Professor of Pharmacology (in the Center for Molecular Recognition and in Physiology and Cellular Biophysics)

Administrative Titles

  • Chief, Division of Molecular Therapeutics
  • Director, Lieber Center for Schizophrenia Research and Treatment

Jonathan A. Javitch obtained his B.S. and M.S. in Biological Sciences at Stanford University. He completed the joint M.D.-Ph.D. program at the Johns Hopkins University School of Medicine where as a graduate student with Solomon Snyder he demonstrated that a key step in the neurotoxicity of MPTP is the uptake of its metabolite MPP+ by the dopamine transporter.

After graduating from Hopkins, Dr. Javitch completed a medical internship and psychiatric residency at the Columbia Presbyterian Hospital and the New York State Psychiatric Institute. He did postdoctoral work on the structure of dopamine receptors with Dr. Arthur Karlin at Columbia University.

Dr. Javitch is currently the Lieber Professor of Experimental Therapeutics in Psychiatry and Professor of Pharmacology in the Center for Molecular Recognition and in Physiology and Cellular Biophysics at the Columbia University College of Physicians and Surgeons, Director of the Lieber Center for Schizophrenia Research and Treatment, and Chief of the Division of Molecular Therapeutics at the New York State Psychiatric Institute.

Gender

  • Male

Research

One main line of research in my laboratory is aimed at understanding the structural bases of agonist and antagonist binding and specificity in the dopamine D2-like receptors and related biogenic amine receptor, how agonist binding is transduced into G protein activation, and the structural basis for G protein-coupled receptor (GPCR) oligomerization and its role in signaling. In the pursuit of these objectives we are carrying out research on the dopamine D2 receptor as well as several other GPCRs. The D2 receptor is the principal target of antipsychotic drugs used in the treatment of schizophrenia.

Other research in my laboratory is focused on determining the structural bases of the transport of substrate by the dopamine transporter and its inhibition by drugs such as cocaine and amphetamine. We are also studying regulation of the trafficking and function of the dopamine transporter and its role in sensitization. Several lines of evidence support the relevance of sensitization to the pathophysiology of schizophrenia, including the ability of amphetamine and other psychostimulants to induce psychosis in normal subjects and the increased sensitivity of patients with schizophrenia to the psychotogenic effects of psychostimulants.

Our laboratory also studies a number of bacterial homologs of the neurotransmitter transporters as model systems for direct structural studies, including X-ray crystallography, EPR spectroscopy, and single-molecule fluorescence spectroscopy, which we are pursuing in collaboration with colleagues. Our work focuses primarily on the molecular and cellular level, and we also are using mice and fruit flies as model systems to probe the relevance of these molecular details to psychostimulant-induced behaviors.

Research Interests

  • G-protein Coupled Receptors: Structural Bases for Pharmacological Specificity and Function
  • Neurotransmitter Transporters: Biophysics, Biochemistry and Regulation
  • Neurobiology of Disease
  • Biophysics/ion Channels
  • Models of Psychiatric Disorders

Grants

PROBING MECHANISMS OF AMPHETAMINE ACTION AT PLASMA MEMBRANE AND VESICULAR TRANSPORTERS IN VITRO AND IN VIVO (Federal Gov)

Apr 1 2017 - Jan 31 2022

THE TRANSPORT CYCLE IN NEUROTRANSMITTER UPTAKE SYSTEMS (BRIDGE 3.1) (Federal Gov)

Sep 24 2015 - Aug 31 2020

MOLECULAR MECHANISMS UNDERLYING THE ANTIDEPRESSANT ACTIONS OF TIANEPTINE (Private)

Jul 1 2017 - Jun 30 2019

THE ROLE OF THALAMIC DOPAMINE D2 RECEPTORS IN COCAINE INTAKE (Federal Gov)

Jul 1 2017 - Jun 30 2018

MOLECULAR MECHANISMS UNDERLYING THE ANTIDEPRESSANT ACTIONS OFTIANEPTINE AND ITS ANALOGS (Private)

Jun 1 2016 - Sep 30 2017

SMFRET INVESTIGATION OF GATING IN A NEUROTRANSMITTER TRANSPORTER HOMOLOG (Federal Gov)

Sep 1 2013 - Aug 31 2017

MOLECULAR DETERMINANTS FOR THE ACTION OF PSYCHOSTIMULANTS (Federal Gov)

Sep 1 2007 - Aug 31 2017

FUNCTIONALLY SELECTIVE D2R S, STRIATAL CIRCUIT FUNCTION AND MOTIVATION (Federal Gov)

May 20 2016 - Mar 31 2017

STRUCTURE AND FUNCTION OF DOPAMINE RECEPTORS (Federal Gov)

Nov 1 2013 - Jul 31 2016

MOLECULAR MECHANISMS OF BACTERIAL HOMOLOGS OF NEUROTRANSMITTER: SODIUM SYMPORTERS (Federal Gov)

Sep 30 2003 - Jun 30 2016

SINGLE MOLECULE IMAGING OF BETA2 ADRENERGIC RECEPTOR ACTIVATION (Federal Gov)

Mar 1 2013 - May 31 2016

STRUCTURE AND FUNCTION OF NEUROTRANSMITTER TRANSPORTERS (Federal Gov)

Mar 1 2011 - Feb 28 2015

DEVELOPMENT AND VALIDATION OF AN IN VIVO PARADIGM TO IMAGE GLUTAMATE TRANSMISSION (Private)

Aug 1 2013 - Jul 31 2014

THE MEMBRANE PROTEIN STRUCTURAL DYNAMICS CONSORTIUM (Federal Gov)

Aug 10 2010 - Jun 30 2014

FUNCTIONAL PROPERTIES OF PROTEIN SEGMENTS IN RECEPTORS AND TRANSPORTERS (Federal Gov)

Apr 1 2009 - Mar 31 2014

NARSAD DISTINGUISHED INVESTIGATOR AWARD (Private)

May 15 2011 - Nov 14 2013

STRUCTURE AND FUNCTION OF NEUROTRANSMITTER TRANSPORTERS (Federal Gov)

Mar 1 2011 - Feb 28 2013

THE MEMBRANE PROTEIN STRUCTURAL DYNAMICS CONSORTIUM (Federal Gov)

Aug 10 2010 - Jun 30 2012

AMPHETAMINE REGULATION OF DOPAMINE TRANSPORT (Federal Gov)

Jul 1 2009 - Jun 30 2011

STRUCTURE AND FUNCTION OF THE DOPAMINE TRANSPORTER (Federal Gov)

Apr 1 2009 - Mar 31 2011

DOPAMINE TRANSPORTER--SUBSTRATE AND COCAINE BINDING SITES (Federal Gov)

Feb 20 1998 - Dec 31 2005

Selected Publications

Selected Publications Since 2011

  • Gallo EF, Salling MC, Feng B, Morón JA, Harrison NL, Javitch JA, Kellendonk C. Upregulation of dopamine D2 receptors in the nucleus accumbens indirect pathway increases locomotion but does not reduce alcohol consumption. Neuropsychopharmacology. 40:1609-1618. doi: 10.1038/npp. (2015).
  • Frederick AL, Yano H, Trifilieff P, Vishwasrao HD, Biezonski D, Mészáros J, Urizar E, Sibley DR, Kellendonk C, Sonntag KC, Graham DL, Colbran RJ, Stanwood GD, Javitch JA. Evidence against dopamine D1/D2 receptor heteromers. Mol Psychiatry. doi: 10.1038/mp.2014.166. (2015).
  • Biezonski DK, Trifilieff P, Meszaros J, Javitch JA, Kellendonk C. Evidence for limited D1 and D2 receptor coexpression and colocalization within the dorsal striatum of the neonatal mouse. J Comp Neurol. 523:1175-1189. doi: 10.1002/cne.23730. (2015).
  • Michino M, Beuming T, Donthamsetti P, Newman AH, Javitch JA, Shi L. What can crystal structures of aminergic receptors tell us about designing subtype-selective ligands? Pharmacol Rev. 67:198-213. doi: 10.1124/pr.114.009944. Review. (2015).
  • Clayton CC, Donthamsetti P, Lambert NA, Javitch JA, Neve KA. Mutation of three residues in the third intracellular loop of the dopamine D2 receptor creates an internalization-defective receptor. J Biol Chem. 289:33663-33675. doi: 10.1074/jbc.M114.605378. (2014).
  • Malinauskaite L, Quick M, Reinhard L, Lyons JA, Yano H, Javitch JA, Nissen P. A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters. Nat Struct Mol Biol. 21:1006-1012. doi: 10.1038/nsmb.2894. (2014).
  • Gaskill PJ, Yano HH, Kalpana GV, Javitch JA, Berman JW. Dopamine receptor activation increases HIV entry into primary human macrophages. PLoS One. 9:e108232. doi: 10.1371/journal.pone.0108232. eCollection. (2014).
  • Lane JR, Donthamsetti P, Shonberg J, Draper-Joyce CJ, Dentry S, Michino M, Shi L, López L, Scammells PJ, Capuano B, Sexton PM, Javitch JA, Christopoulos A. A new mechanism of allostery in a G protein-coupled receptor dimer. Nat Chem Biol. 10:745-752. doi: 10.1038/nchembio.1593. (2014).
  • Gassaway MM, Rives ML, Kruegel AC, Javitch JA, Sames D. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist. Transl Psychiatry. 4:e411. doi: 10.1038/tp.2014.30. (2014).
  • Kazmier K, Sharma S, Quick M, Islam SM, Roux B, Weinstein H, Javitch JA, McHaourab HS. Conformational dynamics of ligand-dependent alternating access in LeuT. Nat Struct Mol Biol. 21:472-479. doi: 10.1038/nsmb.2816. (2014).
  • Dehnes Y, Shan J, Beuming T, Shi L, Weinstein H, Javitch JA. Conformational changes in dopamine transporter intracellular regions upon cocaine binding and dopamine translocation. Neurochem Int. 73:4-15. doi: 10.1016/j.neuint.2014.02.003. (2014).
  • Michino M, Donthamsetti P, Beuming T, Banala A, Duan L, Roux T, Han Y, Trinquet E, Newman AH, Javitch JA, Shi L. A single glycine in extracellular loop 1 is the critical determinant for pharmacological specificity of dopamine D2 and D3 receptors. Mol Pharmacol. 84:854-864. doi: 10.1124/mol.113.087833. (2013).
  • Khelashvili G, LeVine MV, Shi L, Quick M, Javitch JA, Weinstein H. The membrane protein LeuT in micellar systems: aggregation dynamics and detergent binding to the S2 site. J Am C
  • hem Soc. 135:14266-14275. doi: 10.1021/ja405984v. (2013).
  • Gavalas A, Lan TH, Liu Q, Corrêa IR Jr, Javitch JA, Lambert NA. Segregation of family A G protein-coupled receptor protomers in the plasma membrane. Mol Pharmacol. 84:346-352. doi: 10.1124/mol.113.086868. (2013).
  • Trifilieff P, Feng B, Urizar E, Winiger V, Ward RD, Taylor KM, Martinez D, Moore H, Balsam PD, Simpson EH, Javitch JA. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation. Mol Psychiatry. 18(9):1025-1033. doi: 10.1038/mp.2013.57. (2013).
  • Kantcheva AK, Quick M, Shi L, Winther AM, Stolzenberg S, Weinstein H, Javitch JA, Nissen P. Chloride binding site of neurotransmitter sodium symporters. Proc Natl Acad Sci USA, 110:8489-8494. doi: 10.1073/pnas.1221279110. (2013).
  • Pizzo AB, Karam CS, Zhang Y, Ma CL, McCabe BD, Javitch JA. Amphetamine-induced behavior requires CaMKII-dependent dopamine transporter phosphorylation. Mol Psychiatry. 19:279-281. doi: 10.1038/mp.2013.29. No abstract available. (2014).
  • Negri A, Rives ML, Caspers MJ, Prisinzano TE, Javitch JA, Filizola M. Discovery of a novel selective kappa-opioid receptor agonist using crystal structure-based virtual screening. J Chem Inf Model. 53:521-526. doi: 10.1021/ci400019t. (2013).
  • Simpson N, Maffei A, Freeby M, Burroughs S, Freyberg Z, Javitch J, Leibel RL, Harris PE. Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro. Mol Endocrinol. 26:1757-1772. (2012).
  • Rives ML, Rossillo M, Liu-Chen LY, Javitch JA. 6'-Guanidinonaltrindole (6'-GNTI) is a G protein-biased κ-opioid receptor agonist that inhibits arrestin recruitment. J Biol Chem. 287:27050-27054. doi: 10.1074/jbc.C112.387332. (2012).
  • Pizzo AB, Karam CS, Zhang Y, Yano H, Freyberg RJ, Karam DS, Freyberg Z, Yamamoto A, McCabe BD, Javitch JA. The membrane raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila. Mol Psychiatry. 18:824-833. doi: 10.1038/mp.2012.82. (2013).
  • Newman AH, Beuming T, Banala AK, Donthamsetti P, Pongetti K, LaBounty A, Levy B, Cao J, Michino M, Luedtke RR, Javitch JA, Shi L. Molecular determinants of selectivity and efficacy at the dopamine D3 receptor. J Med Chem. 55:6689-6699. doi: 10.1021/jm300482h. (2012).
  • Quick M, Shi L, Zehnpfennig B, Weinstein H, Javitch JA. Experimental conditions can obscure the second high-affinity site in LeuT. Nat Struct Mol Biol. 19:207-211. doi: 10.1038/nsmb.2197. (2012).
  • Rappold PM, Cui M, Chesser AS, Tibbett J, Grima JC, Duan L, Sen N, Javitch JA, Tieu K. Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc Natl Acad Sci USA. 108:20766-71. doi: 10.1073/pnas.1115141108. (2011).
  • Altman RB, Terry DS, Zhou Z, Zheng Q, Geggier P, Kolster RA, Zhao Y, Javitch JA, Warren JD, Blanchard SC. Cyanine fluorophore derivatives with enhanced photostability. Nat Methods. 9:68-71. doi: 10.1038/nmeth.1774. (2011).
  • Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, Peterson S, Yadav PN, Huang XP, Feng B, Jensen NH, Che X, Bai X, Frye SV, Wetsel WC, Caron MG, Javitch JA, Roth BL, Jin J. Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc Natl Acad Sci USA. 108:18488-18493. doi: 10.1073/pnas.1104807108. (2011).
  • Trifilieff P, Rives ML, Urizar E, Piskorowski RA, Vishwasrao HD, Castrillon J, Schmauss C, Slättman M, Gullberg M, Javitch JA. Detection of antigen interactions ex vivo by proximity ligation assay: endogenous dopamine D2-adenosine A2A receptor complexes in the striatum. Biotechniques. 51:111-118. doi: 10.2144/000113719. (2011).
  • Urizar E, Yano H, Kolster R, Galés C, Lambert N, Javitch JA. CODA-RET reveals functional selectivity as a result of GPCR heteromerization. Nat Chem Biol. 7:624-630. doi: 10.1038/nchembio.623. (2011).
  • Zhao Y, Terry DS, Shi L, Quick M, Weinstein H, Blanchard SC, Javitch JA. Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue. Nature. 474:109-113. doi: 10.1038/nature09971. (2011).
  • Cremona ML, Matthies HJ, Pau K, Bowton E, Speed N, Lute BJ, Anderson M, Sen N, Robertson SD, Vaughan RA, Rothman JE, Galli A, Javitch JA, Yamamoto A. Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT. Nat Neurosci. 14:469-77. doi: 10.1038/nn.2781. Erratum in: Nat Neurosci. 2011 Dec;14:1617. (2011).
  • Shan J, Javitch JA, Shi L, Weinstein H. The substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transporter. PLoS One. 6:e16350. doi: 10.1371/journal.pone.0016350. (2011).
  • Johnston JM, Aburi M, Provasi D, Bortolato A, Urizar E, Lambert NA, Javitch JA, Filizola M. Making structural sense of dimerization interfaces of delta opioid receptor homodimers. Biochemistry. 50:1682-1690. doi: 10.1021/bi101474v. (2011).