F A C U L T Y   P R O F I L E 

Harrison

JAVITCH, JONATHAN A, M.D. , PH.D.
Lieber Professor of Experimental Therapeutics in Psychiatry and Professor of Pharmacology (in the Center for Molecular Recognition and in Physiology & Cellular Biophysics)

G-protein coupled receptors: structural bases for pharmacological specificity and function; neurotransmitter transporters: biophysics, bicochemistry and regulation.

Office: Physicians & Surgeons| 11th Floor | Room 401
Telephone: 212.305.7308
Fax: 212.305.5594
Email:
jaj2@columbia.edu


Current Research
Dr. Javitch’s 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. The laboratory is also studying the function and regulation of dopamine transporter and dopamine receptors in the fruit fly Drosophila melanogaster, where they have developed approaches to translate between molecular mechanisms and whole organism behavior using the power of fly genetics and multiphoton imaging.


Selected Publications

1.Guo W, Shi L, Filizola M, Weinstein H, Javitch JA. (2005) Crosstalk in G protein-coupled receptors: changes at the transmembrane homodimer interface determine activation. Proc Natl Acad Sci U S A 102(48):17499-17500

2. Quick M, Yano H, Goldberg NR, Duan L, Beuming T, Shi L, Weinstein H, Javitch JA. (2006) State-dependent conformations of the translocation pathway in the tyrosine transporter Tyt1, a novel neurotransmitter:sodium symporter from Fusobacterium nucleatum. J Biol Chem. 281(36):26444-26454

3. Beuming T, Shi L, Javitch JA, Weinstein H. (2006) A comprehensive structure-based alignment of prokaryotic and eukaryotic neurotransmitter/Na+ symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function. Mol Pharmacol. 70(5):1630-1642

4. Fog JU, Khoshbouei H, Holy M, Owens WA, Vaegter CB, Sen N, Nikandrova Y, Bowton E, McMahon DG, Colbran RJ, Daws LC, Sitte HH, Javitch JA, Galli A, Gether U. (2006) Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. Neuron 51(4):417-429

5. Quick M, Javitch JA. (2007) Monitoring the function of membrane transport proteins in detergent-solubilized form. Proc Natl Acad Sci U S A 104(9):3603-3608

6. Erreger K, Grewer C, Javitch JA, Galli A. (2008) Currents in response to rapid concentration jumps of amphetamine uncover novel aspects of human dopamine transporter function. J Neuroscience 28(4):976-989

7. Guo W, Urizar E, Kralikova M, Mobarec JC, Shi L, Filizola M, Javitch JA. (2008) Dopamine D2 receptors form higher order oligomers at physiological expression levels. EMBO J :July 31 (In Press)

8. Beuming T, Kniazeff J, Bergmann ML, Shi L, Gracia L, Raniszewska K, Newman AH, Javitch JA, Weinstein H, Gether U, Loland CJ. (2008) The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat. Neuroscience 11(7):780-789

9. Klewe IV, Nielsen SM, Tarpo L, Urizar E, Dipace C, Javitch JA, Gether U, Egebjerg J, Christensen KV. (2008) Recruitment of beta-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling. Neuropharmacology 54(8):1215-1222

10. Shi L, Quick M, Zhao Y, Weinstein H, Javitch JA. (2008) The mechanism of a neurotransmitter:sodium symporter--inward release of Na+ and substrate is triggered by substrate in a second binding site. Mol. Cell. 30(6):667-677

11. Single-molecule dynamics of gating in a neurotransmitter transporter homologue. Zhao Y, Terry D, Shi L, Weinstein H, Blanchard SC, Javitch JA. Nature. 2010 May 13;465(7295):188-93.

12. Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:sodium symporters. Claxton DP, Quick M, Shi L, de Carvalho FD, Weinstein H, Javitch JA, McHaourab HS. Nat Struct Mol Biol. 2010 Jul;17(7):822-9. Epub 2010 Jun 20.

13. Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Albizu L, Cottet M, Kralikova M, Stoev S, Seyer R, Brabet I, Roux T, Bazin H, Bourrier E, Lamarque L, Breton C, Rives ML, Newman A, Javitch J, Trinquet E, Manning M, Pin JP, Mouillac B, Durroux T. Nat Chem Biol. 2010 Aug;6(8):587-94. Epub 2010 Jul 11.

14. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC. Science. 2010 Nov 19;330(6007):1091-5.

15. The substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transporter. Shan J, Javitch JA, Shi L, Weinstein H. PLoS One. 2011 Jan 27;6(1):e16350.

16. Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT. 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. Nat Neurosci. 2011 Apr;14(4):469-77. Epub 2011 Mar 13.

17. Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue. Zhao Y, Terry DS, Shi L, Quick M, Weinstein H, Blanchard SC, Javitch JA. Nature. 2011 Jun 2;474(7349):109-13. Epub 2011 Apr 24.

18. 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, 2011 Jul 24;7(9):624-30.