F A C U L T Y P R O F I L E
JAVITCH, JONATHAN. M.D., Ph.D.
Structure, function and regulation of G-Protein-Coupled receptors and neurotransmitter transporters.
Office: Physicians & Surgeons | 11th floor | Room 401
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.
His research focuses on the structure, function and regulation of G protein-coupled receptors and neurotransmitter transporters, with an emphasis on dopamine D2 receptor and dopamine transporter, the targets, respectively, for antipsychotic drugs and psychostimulants, using biochemical and biophysical approaches to elucidate molecular mechanisms of drug action, receptor signaling and sodium-coupled transport. His studies of GPCRs are uncovering unappreciated regulation of signaling by heteromeric complexes of receptors, raising the possibility of a novel approach to drug design and screening. In collaboration with leading experts in the field, his laboratory is also pursuing single molecule fluorescence spectroscopy, electron paramagnetic resonance spectroscopy, and crystallographic studies of bacterial homologs of neurotransmitter transporters to explicate the mechanisms of sodium-coupled transport and the actions of antidepressant drugs that inhibit transport. He is also studying the function and regulation of dopamine transporter and dopamine receptors in the fruit fly Drosophila melanogaster, in which his laboratory has developed approaches to translate between molecular mechanisms and whole organism behavior using the power of fly genetics.
1. Zhao, Y., Terry, D., Shi, L., Weinstein, H., Blanchard, S.C., Javitch, J.A. Single-molecule dynamics of gating in a neurotransmitter transporter homolog. Nature, 465:188-93 (2010).
2. Chien,E.Y.T., Liu, W., Zhao, Q.W., Katritch, V., Han, G.W., Hanson, M.A.,Shi, L., Newman, A.H., Javitch, J.A., Cherezov, V., Stevens, R.C. Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist. Science, 30:1091-5 (2011).
3. 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 (2011).
4. Zhao, Y., Terry, D., Shi, L., Quick, M., Weinstein, H., Blanchard, S.C., Javitch J.A. Substrate-modulated gating dynamics in a sodium-coupled transporter. Nature 474:109-13 (2011).
5. Urizar, E., Yano, H., Kolster, R., Gales, C., Lambert, N., Javitch, J.A. CODA-RET reveals functional selectivity as a result of GPCR heteromerization. Nat Chem Biol, 7:624-30 (2011).
6. 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. 19:207-11 (2012).
7. Altman RB, Terry DS, Zhou A, Zheng Q, Geggier P, Kolster RA, Zhao Y, Javitch JA, Warren D, Blanchard SC. Cyanine fluorophore derivatives with enhanced photostability. Nat Methods, 9:68-71 (2012).
8. 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. 55:6689-99 (2012).
9. 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. [Epub ahead of print] (2012).
10. 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. 287:27050-4 (2012) .
11. 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. 26:1757-72 (2012).
12. Pizzo AB, Karam CS, Zhang Y, Ma CL, McCabe BD, Javitch JA. Amphetamine-induced behavior requires CaMKII-dependent dopamine transporter phosphorylation. Mol Psychiatry. 2013 Mar 19. doi: 10.1038/mp.2013.29. [Epub ahead of print] PMID: 23508128
13. 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. 2013 Mar 13. [Epub ahead of print] PMID: 23461591
14. 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 U S A. 2013 May 21;110(21):8489-94
15. 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. 2013 Sep;18(9):1025-33
16. 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. 2013 Sep;84(3):346-52
17. 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 Chem Soc. 2013 Sep 25;135(38):14266-75
18. 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. 2013 Sep 23. [Epub ahead of print]