Stephen S. G. Ferguson
Professor
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Canada Research Chair in Molecular Neurobiology |
My research program focuses on unraveling the basic molecular mechanisms involved in the regulation of G protein-coupled receptor (GPCR) activity. My laboratory utilizes a combination of molecular pharmacological and cell biological techniques to examine the role of small G proteins, GRKs, b-arrestins and a wide variety of other receptor interacting proteins in the signaling, endocytosis and intracellular trafficking of GPCRs. The purpose of these studies is gain a better understanding of differences and similarities in the molecular mechanisms involved in signaling, desensitization and resensitization of distinct GPCRs. Consequently, our efforts are currently focus on four model GPCRs: metabotropic glutamate (mGluRs) and corticotropin releasing factor (CRF) receptors in the central nervous system as well as angiotensin II type 1A receptors (AT1AR) and formyl-Met Leu Phe (fMLP) receptors in the cardiovascular system. Our understanding of the complicated array of GPCR regulatory mechanisms has evolved rapidly as the consequence of our studies of protein expression in heterologous cell culture systems. Although these systems are extremely important for the description and characterization of novel signal transduction mechanisms and protein-protein interactions, the relative physiological consequence of these pathways and interactions is certain to depend upon cellular context and environment. Consequently, we have expanded our studies to primary neuronal cell culture systems and have begun the development of transgenic and knockout mouse models to study receptor regulation in vivo.
Seachrist, J. L., Laporte, S. A., Dale, L. B., Babwah, A. V., Caron, M. G., Anborgh, P. H., and Ferguson, S. S. G. (2002) Rab5 association with the angiotensin II Type 1A receptor promotes Rab5 GTP-binding and vesicular fusion. J. Biol. Chem. 277, 679-685
Dhami, G. K., Anborgh, P. H., Dale, L. B., Sterne-Marr, R., and Ferguson, S. S. G. (2002) Phosphorylation-independent regulation of metabotropic glutamate receptor signaling by G protein-coupled receptor kinase 2. J. Biol. Chem. 277, 25266-25272
Bhattacharya, M., Anborgh, P. H., Babwah, A. V., Dale, L. B., Dobransky, T., Benovic, J. L., Feldman, R. D.,Verdi J. M., Rylett, R. J., and Ferguson, S. S. G. (2002) b-Arrestin regulates a RalGDS-Ral effector pathway mediating cytoskeletal reorganization. Nat. Cell Biol. 4, 547-555.
Dhami, G. K., Dale, L. B., Anborgh, P.H., O’Connor-Halligan, K. E., Sterne-Marr, R., and Ferguson, S. S. G. (2004) G Protein-coupled receptor kinase 2 RGS homology domain binds to both metabotropic glutamate receptor 1a and Gaq to attenuate signaling. J. Biol. Chem. 279, 16614-16620.
Dale, L. B., Seachrist, J. L., Babwah, A. V., and Ferguson, S. S. G. (2004) Regulation of angiotensin II 1A receptor intracellular retention, degradation and recycling by Rab5, Rab7 and Rab11 GTPases. J. Biol. Chem. 279, 13110-13118.
Bhattacharya, M., Babwah, A. V., Godin, C., Anborgh, P. H., Dale, L. B., Poulter, M. O. and Ferguson, S. S. G. (2004) Ral and phospholipase D2-dependent pathway for constitutive metabotropic glutamate receptor endocytosis. J. Neurosci. 24, 8752-8761.
Anborgh, P. H., Godin, C., Pampillo, M. ., Dhami, G. K., Dale, L. B., Cregan, S. P., Truant, R., and Ferguson, S. S. G. (2005) Inhibition of metabotropic glutamate receptor signalling by the huntingtin binding protein optineurin. J. Biol. Chem. 280, 34840-34848.
Policha, A., Daneshtalab, N., Chen, L., Dale L. B., Altier, C., Khosravani, H., Thomas, W. G., Zamponi, G. W., and Ferguson S. S. G. (2006) Role of angiotensin II type 1A receptor phosphorylation, phospholipase D, and extracellullar calcium in isoform specific protein kinase C membrane translocation responses. J. Biol. Chem. 281, 26340-26349.
Ferguson S. S. G. (2007) Phosphorylation-independent attenuation of GPCR signaling. Trends Pharmacol. Sci. 28, 173-179.
Ribeiro, F. M., Ferreira, L. T., Paquet, M, Cregan, T., Ding, Q., Gros, R., and Ferguson, S. S. G. (2009) Phosphorylation-independent regulation of metabotropic glutamate receptor 5 desensitization and internalization by G protein-coupled receptor kinase 2 in striatal neurons. J. Biol. Chem. 284, 23444-23453
Ribeiro, F. M., Paquet, M., Ferieira, L. T., Cregan, T., Cregan, S. P., and Ferguson S. S. G. (2010) Metabotropic glutamate receptor 1/5 mediated cell signaling pathways are altered in a mouse model of Huntington’s disease. J. Neurosci. 30, 316-324.
Godin C., Ferreira, L. T., Dale, L. B., Gros, R., Cregan, S. P. and Ferguson S. S. G. (2010) RalGDS and Ral dependent coupling of the angiotensin II type 1 receptor to the activation of phospholipaseC-d1. Mol. Pharmacol. 77, 388-395.
Magalhaes, A., Holmes, K., Dale, L. B., Drysdale, L., Comps-Agrar, L., Lee, D. K, Yadav, P. N., Poulter M. O., Roth, B. L., Pin, J.-P., Anisman, H. and Ferguson S. S. G. (2010) CRF receptor1 regulates anxiety behaviour via sensitization of 5-HT2 receptor signaling. Nat. Neurosci. 13, 622-629.
