JAVITCH, JONATHAN. M.D., Ph.D. Professor of Physiology & Cellular Biophysics, and Psychiatry and Pharmacology Structure, function and regulation of G-Protein-Coupled receptors and neurotransmitter transporters. Office: Physicians & Surgeons | 11th floor | Room 401 Telephone: 212.305.7308 Fax: 212.305.5594 Email:jaj2@columbia.edu

Current Research

Jonathan A. Javitch attended Stanford University where he obtained a B.S. and M.S. in Biological Sciences in 1980. In 1986 he completed the joint M.D.-Ph.D. program at the Johns Hopkins University School of Medicine, where as a graduate student with Dr. Solomon Snyder he demonstrated that a key step in the ParkinsonŒs-like 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 currently is a tenured Associate Professor of Psychiatry and Pharmacology in the Center for Molecular Recognition at Columbia University. His laboratory focuses on understanding the structure and function of G-protein coupled receptors and neurotransmitter transporters, with a particular focus on dopamine receptors and transporter, the targets for antipsychotic drugs and cocaine, respectively.

Selected Publications

Han, Y., Moreira, I.S., Urizar, E., Weinstein, H., Javitch, J.A. Allosteric communication between protomers of dopamine Class A GPCR dimers modulates activation. Nature Chemical Biology, in press.

Goodwin, J.S., Larson, G.A., Swant, J., Sen, N., Javitch, J.A., Zahniser, N.R., De Felice, L.J., Khoshbouei, H. Amphetamine and methamphetamine differentially affect dopamine transporters in vitro and in vivo. J Biol Chem. 284:2978-89 (2009).

Guptaroy, B., Zhang, M., Bowton, E., Binda, F., Shi, L., Weinstein, H., Galli, A., Javitch, J.A., Neubig, R.R., Gnegy, M.E. A juxtamembrane mutation in the N-terminus of the dopamine transporter induces preference for an inward-facing conformation. Mol Pharmacol, 75:514-24 (2009).

Ferré, S., Baler, R., Bouvier, M., Caron, M.G., Devi, L.A., Durroux, T., Fuxe, K., George, S.R., Javitch, J.A., Lohse, M.J., Mackie, K., Milligan, G., Pfleger, K.D., Pin, J.P., Volkow, N.D., Waldhoer, M., Woods, A.S., Franco, R. Building a new conceptual framework for receptor heteromers. Nature Chem Biol. 5:131-4 (2009).

Quick, M., Lund Winther, A.-M., Shi, L., Nissen, P., Weinstein, H., Javitch, J.A. Binding of an octylglucoside detergent molecule in the second substrate (S2) site of LeuT establishes an inhibitor-bound conformation. Proc. Natl. Acad. Sci. USA, 106:5563-8 (2009).

Namkung, Y., Dipace, C., Javitch, J.A., Sibley, D.R. G protein-coupled receptor kinase-mediated phosphorylation regulates post-endocytic trafficking of the D2 dopamine receptor. J Biol Chem. (2009) Mar 30. [Epub ahead of print].

Erreger, K. Grewer, C., Javitch, J.A., Galli, A. 2008. Currents in response to rapid concentration jumps of amphetamine uncover novel aspects of human dopamine transporter function, J Neurosci, 27:976-89.

Skrabanek, L., Murcia, M., Bouvier, M., Devi, L., George, S.R., Lohse, M.J., Milligan, G., Neubig, R., Palczewski, K., Parmentier, M., Pin, J.P., Vriend, G., Javitch, J.A., Campagne, F., Filizola, M. 2007. Requirements and ontology for a G protein-coupled receptor oligomerization knowledge base. BMC Bioinformatics. 8:177.

Erreger, K. Grewer, C., Javitch, J.A., Galli, A. Currents in response to rapid concentration jumps of amphetamine uncover novel aspects of human dopamine transporter function, J Neurosci, 27:976-89 (2008).

Klewe, I.V., Nielsen, S.M., Tarpø, L., Urizar, E., Dipace, C., Javitch, J.A., Gether, U., Egebjerg, J., Christensen, K.V. Recruitment of beta-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling, Neuropharmacology 54(8):1215-22 (2008).

Kniazeff, J., Shi, L., Loland, C.J., Javitch, J.A., Weinstein, H., Gether, U. An intracellular interaction network regulates conformational transitions in the dopamine transporter. J Biol Chem. 283:17691-701 (2008).

Binda F, Dipace C, Bowton E, Doughty SE, Lute BJ, Fog JU, Zhang M, Sen N, Colbran RJ, Gnegy ME, Gether U, Javitch JA, Erreger K, Galli A. Syntaxin1A Interaction with the Dopamine Transporter Promotes Amphetamine-Induced Dopamine Efflux. Mol Pharmacol. (2008 Jul 10).

Girgis, R.R., Javitch, J.A., Lieberman, J.A. Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway. Mol Psychiatry (2008 Apr 15).

Beuming T, Kniazeff J, Bergmann ML, Shi L, Gracia L, Raniszewska K, Newman AH, Javitch JA, Weinstein H, Gether U, Loland CJ. The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat Neurosci. 11:780-9 (2008).

Lute BJ, Khoshbouei H, Saunders C, Sen N, Lin RZ, Javitch JA, Galli A. PI3K signaling supports amphetamine-induced dopamine efflux. Biochem Biophys Res Commun. 372:656-61 (2008).

Lieberman, J.A., Javitch, J.A., Moore, H. Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry. Am J Psychiatry. 165:931-6. (2008).

Shi, L., Quick, M., Zhao, Y., Weinstein, H., Javitch, J.A. The mechanism of a neurotransmitter:sodium symporter – inward release of Na+ and substrate is triggered by substrate in a second binding site, Molecular Cell, 30:667-77 (2008).

Guo, W., Urizar, E., Kralikova, M., Mobarec, J.C., Shi, L., Filizola, M., Javitch, J.A. Dopamine D2 receptors form higher order oligomers at physiological expression levels. EMBO J., 27:2293-304 (2008).

Zomot, E., Bendahan, A., Quick, M., Zhao, Y., Javitch, J.A., Kanner, B.I. 2007. Mechanism of chloride interaction with neurotransmitter:sodium symporters, Nature, 449:726-730.

Zapata, A., Kivell, B., Han, Y., Javitch, J.A., Bolan, E.A., Kuraguntla, D., Jaligam, V., Oz, M., Jayanthi, L.D., Samuvel, D.J., Ramamoorthy, S., Shippenberg, T.S. 2007. Regulation of dopamine transporter function and cell surface expression by D3 dopamine receptors. J Biol Chem, 282:35842-54.

Wei, Y., Williams, J., Javitch, J.A., Galli, A., Saunders, C. 2007. Dopamine transporter activity mediates amphetamine-induced inhibition of Akt through a CamKII dependent mechanism, Mol Pharmacol. 71:835-42.

Bolan, E.A., Kivell, B., Jaligam, V., Oz, M., Jayanthi, L.D., Han, Y., Sen, N., Urizar, E., Gomes, I., Devi, L.A., Ramamoorthy, S., Javitch, J.A., Zapata, A., and Shippenberg, T.S. 2007. D2 Receptors Regulate Dopamine Transporter Function Via an ERK 1/2-Dependent and PI3 Kinase-Independent Mechanism, Mol Pharmacol. Jan. 31 e-pub.

Pin, J.P., Neubig, R., Bouvier, M., Devi, L., Filizola, M., Javitch, J.A., Lohse, M.J., Milligan, G., Palczewski, K., Parmentier, M., and Spedding, M. 2007. International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the Recognition and Nomenclature of G Protein-Coupled Receptor Heteromultimers. Pharmacol Rev. 59:5-13.

Quick, M. and Javitch, J.A. 2007. Monitoring the activity of membrane transport proteins in detergent-solubilized form, Proc. Natl. Acad. Sci. USA. 104: 3603-3608.

Kahlig, K.M., Lute, B.J., Wei, Y., Loland, C.J., Gether, U., Javitch, J.A., and Galli, A. 2006. Regulation of Dopamine Transporter Trafficking by Intracellular Amphetamine. Mol Pharmacol., 70:542-548.

Shi, L., and Javitch, J.A. 2006. A role for information collection, management, and integration in structure-function studies of G-protein coupled receptors. Curr Pharm Des. 12:1771-83.

Urban, J.D., Clarke, W.P., von Zastrow, M., Nichols, D.E., Kobilka, B.K., Weinstein, H., Javitch, J.A., Roth, B.L., Christopoulos, A., Sexton, P., Miller, K., Spedding, M., and Mailman, R.B. 2006. Functional selectivity and classical concepts of quantitative pharmacology, J Pharmacol Exp Ther. 320:1-13.

Fog, J.U., Khoshbouei, H., Holy, M., Owen, W.A., Bjerggaard, C., Sen, N., Nikandrova, Y., Bowton, E., McMahon, D.G., Colbran, R.J., Daws, L.C., Sitte, H.H., Javitch, J.A., Galli, A., and Gether, U. 2006. Calmodulin kinase II interacts with the dopamine transporter C-terminus to regulate amphetamine-induced reverse transport, 51:417-29. Neuron.

Quick, M., Yano, H., Goldberg, N., Duan, L., Beuming. T., Shi, L., Weinstein, H., and Javitch, J.A. 2006. State-dependent conformations of the translocation pathway in the tyrosine transporter Tyt1, a novel neurotransmitter: sodium symporter, J. Biol. Chem., 281:26444-26454.

Beuming, T., Shi, L., Javitch, J.A., and 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., 70:1630-42.

Guo, W., Shi, L., Filizola, M., Weinstein, H., and Javitch, J.A. 2005. Crosstalk in G protein-coupled receptors: Changes at the transmembrane homodimer interface determine activation., Proc. Natl. Acad. Sci. USA, 102:17495-500.

Kahlig, K.M., Binda, F., Khoshbouei, H., Blakely, R.D., McMahon, D.G., Javitch, J.A., and Galli, A. 2005. Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci 102:3495-500.

Garcia, B.G., Wei, Y., Moron, J.A., Lin, R.Z., Javitch, J.A., and Galli, A. 2005. Akt is essential for insulin modulation of amphetamine-induced human dopamine transporter cell-surface redistribution. Mol Pharmacol.68:102-9.

Sonders, M.S., Quick, M., and Javitch, J.A. 2005. How did the neurotransmitter cross the bilayer? A closer view. Curr Opin Neurobiol. 15:296-304. Review.

Kniazeff, J., Loland, C.J., Goldberg, N., Quick, M., Das, S., Sitte, H.H., Javitch, J.A., and Gether, U. 2005. Intramolecular cross-linking in a bacterial homolog of mammalian SLC6 neurotransmitter transporters suggests an evolutionary conserved role of transmembrane segments 7 and 8. Neuropharmacology. 49:715-23.

Sen, N., Shi, L., Beuming, T., Weinstein, H., and Javitch, J.A. 2005. A pincer-like configuration of TM2 in the human dopamine transporter is responsible for indirect effects on cocaine binding. Neuropharmacology. 49(6):780-90.