Scripps Research Joint Appointments

Associate Professor, Department of Metabolism & Aging
Faculty, Graduate Program

Research Focus

The main emphasis of the research in the laboratory is on the fundamental principles that regulate signaling via G protein coupled receptors (GPCR). GPCRs mediate a vast variety of critical biological processes ranging from proliferation and motility to cellular reception and excitability. GPCR signaling pathways are of particular importance for the nervous system function where they control many fundamental processes including excitability, differentiation, sensory perception, and synaptic transmission. Importantly, but not surprisingly, even a subtle imbalance in GPCR signaling often leads to the most profound nervous system disorders ranging from blindness and cognitive problems to grave neurological diseases.

Specifically, our laboratory is interested in understanding the intricate regulatory dynamics of G protein pathways in the following two neuronal systems.

• Basal ganglia where G proteins mediate reward behavior and movement coordination underlying not only addictive effects of abused drugs such as opioids and cocaine but also dysfunctions observed in movement disorders such as Parkinson's disease, Huntington’s disease, Tourette syndrome, and tardive dyskinesia.
• Retina where G protein signaling systems of primary sensory neurons, photoreceptors, and downstream ON-bipolar cells act in tandem to generate responses to light and synaptically encode them to enable our vision. Dysfunctions in these processes are known to be the leading causes of a range of ocular pathologies including macular degeneration and congenital night blindness.

Much of our current efforts are focused on a family of key regulators of GPCR signaling pathways, the Regulator of G protein Signaling (RGS) proteins. RGS proteins constitute a large family of proteins that promote G protein inactivation by facilitating their GTP hydrolysis thus ensuring timely inactivation of the GPCR responses.  Many members of the RGS family have been clinically linked to human disease conditions that have been recapitulated in the genetic mouse models.  Serving as a central control point in GPCR signaling cascades, RGS proteins hold great promises as targets for the drug development. This brings the major emphasis of our research on elucidating molecular and cellular mechanisms of RGS proteins function in cellular signaling in addition to the efforts to uncover novel regulatory principles.

Research directions in the laboratory include discovery and characterization of novel G protein regulators, delineation of protein-protein interactions, feedback mechanisms, and logistics of signaling pathway organization. In our research, we use a range of multidisciplinary approaches involving identification of components of signaling complexes by proteomics, measurement of protein functional activity by in vitro enzyme kinetics, analysis of synthesis, trafficking and degradation of signaling proteins in cell culture and behavioral characterization of genetic mouse models with altered components of G protein signaling machinery.

Education

B.Sc., Biochemistry, Samara State University, Russia, 1996
M.Sc., Molecular Biology, Pushchino State University, Russia, 1998
Ph.D., Molecular Biology, Institute of Protein Research, Russian Academy of Sciences, 2000

Awards & Professional Activities

1998 European Academy Prize in Biology
1999 Russian Biochemical Society Award
2002 American Heart Association Fellowship
2004 Knights Templar Foundation Award
2008 McKnight Land-Grant Professorship

Selected References

Posokhova E., Song H., Belcastro M., Higgins L., Bigley L.R., Michaud N.A., Martemyanov K.A., Sokolov M. (2011) Disruption of the chaperonin containing TCP-1 function in rods affects multiple protein networks and arrests outer segment morphogenesis. Mol Cell Proteom. 10, M110.000570

Posokhova E., Wydeven N., Allen K.L., Wickman K., Martemyanov K.A. (2010) RGS6/Gb5 complex accelerates IKACh gating kinetics in atrial myocytes and modulates parasympathetic regulation of heart rate. Circ. Res. 107, 1350-1354

Xie K., Allen K.L., Kourrich S., Colón-Saez J., Thomas, M.J., Wickman K., Martemyanov K.A. (2010) Gbeta5 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling. Nature Neuroscience 13, 661-663

Cao Y., Kolesnikov A.V., Masuho I., Kefalov V.J., Martemyanov K.A. (2010) Membrane anchoring subunits specify selective regulation of RGS9/Gb5 GAP complex in photoreceptor neurons. J. Neurosci. 30, 13784-13793

Roloff A.M., Anderson G.R., Martemyanov K.A., Thayer S.A. (2010) Homer 1a gates the induction mechanism for endocannabinoid-mediated synaptic plasticity. J. Neurosci. 30, 3072-3081

Posokhova E., Uversky V., Martemyanov K.A. (2010) Proteomic identification of Hsc70 as a mediator of RGS9-2 degradation by in vivo interactome analysis. J. Proteome Res. 9, 1510-1521

Anderson G.R., Cao Y., Davidson S., Truong H.V., Pravetoni M., Thomas M., Wickman K., Giesler G.J.Jr., Martemyanov K.A. (2010) R7BP complexes with RGS9-2 and RGS7 in the striatum differentially control motor learning and locomotor responses to cocaine. Neuropsychopharmacology 35, 1040-1050

Cao Y., Masuho I., Okawa H., Xie K, Asami J., Kammermeier P., Furukawa T., Inoue Y., Sampath A.P., Martemyanov K.A. (2009) Retina specific GTPase accelerator RGS11/Gb5S/R9AP is a constitutive heterotrimer selectively targeted to mGluR6 in ON-bipolar neurons. J. Neurosci. 29, 9301-9313

Anderson, G.R., Posokhova E., Martemyanov K.A. (2009) The R7 RGS protein family: multi-subunit regulators of neuronal G protein signaling. Cell Biochem. Biophys. 54, 33-46

Hooks S., Martemyanov K., and Zachariou, V. (2008) A role of RGS proteins in drug addiction. Biochem. Pharmacol. 75, 76-84

Links

Department of Neuroscience