Stephen S. G. Ferguson, Scientist, Molecular Brain Research Group, Professor, Department of Physiology and Pharmacology
My laboratory studies the functional regulation and activity of G protein-coupled receptors (GPCRs), which represent the largest and most significant class of membrane receptor proteins. These receptors are the targets of more than 50% of the drugs prescribed to treat human disease. My research program focuses on understanding how the activity of these receptors can be regulated under both normal physiological and pathophysiological conditions. Consequently, we are focused on investigating how proteins expressed within cells function to regulate not only the activation of these receptors, but how they contribute to the desensitization and trafficking of GPCRs. In doing so, we hope to identify novel drug targets for the treatment of disease. At this time, our efforts are primarily focused on the role of metabotropic glutamate receptor signaling in Huntington’s disease and Prion protein biology, the regulation of serotonin receptor activity by corticotrophin releasing factor receptors in response stress with a goal of understanding the effect stress has on anxiety and depression behaviours, as well as understanding the molecular changes in GPCR signaling associated with hypertension. These studies are performed in heterologous cell cultures, primary neurons, GRK2 knockdown mice, metabotropic glutamate receptor knockout mice and in mutant huntingtin knockin mouse models.
Research Questions and Disease Implications
Understanding the mechanisms underlying the regulation of metabotropic glutamate receptor signal transduction.
Glutamate is the major excitatory neurotransmitter in the brain and plays an important role in regulate learning, memory, reward and movement. Alterations in glutamate-mediated signaling in the brain have been liked to psychiatric diseases such as schizophrenia and drug addiction and glutamate-stimulated cell death is thought to play an important role in stroke, Alzheimer’s and Huntington’s Disease.
Understanding the regulation of serotonin receptors by corticotropin releasing factor receptors.
Serotonin receptors represent important targets for the treatment of anxiety and depression, whereas corticotropin releasing factor receptors modulate stress in response to anxiety. It is now recognized that stress and anxiety are important factors that predispose to major depression disorders.
Understanding the role of GRK2 in hypertension.
G protein-coupled receptor kinases (GRKs) play an important role in regulating the activity of G protein-coupled receptors expressed in the vaculature that are the primary targets for drugs that treat hypertension. GRK expression is likely to play an important role in regulating whether these drugs successfully alter receptor signaling.
- Ph.D., McGill University, Montreal, Quebec
- B.Sc., McGill University, Montreal, Quebec
• Howard Hughes Medical Institute, Duke University (1994-1997)
• Faculty Scholar, 2010-2012
• Dean’s Award of Excellence, 2010
• Career Investigator Award 1st Renewal, Heart and Stroke Foundation of Ontario, 2008
• Career Investigator Award, Heart and Stroke Foundation of Ontario, 2003
• Canada Research Chair (Tier 1), 2006
• Canada Research Chair (Tier 2), 2001
• Rick Gallop Award, Heart and Stroke Foundation of Ontario, 2006
• Pharmacological Society of Canada Senior Investigator Award, 2005
• Pharmacological Society of Canada Young Investigator Award,2001
• Canada’s Top 40 under 40, 2004
• Dean’s Award of Excellence, 2004
• Premier’s Research Excellence Award, 2000
• McDonald Scholarship Award Heart and Stroke Foundation of Canada,1998
• Esseltine, J. L., Dale, L., B., and Ferguson, S. S. G. (2011) Rab GTPases compete for angiotensin II type I receptor binding and differentially influence receptor dephosphorylation and desensitization. Mol. Pharmacol. 79, 175-184.
• 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.
• 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-1. Mol. Pharmacol. 77, 388-395.
• 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.
• Ferguson S. S. G. (2007) Phosphorylation-independent attenuation of GPCR signaling. Trends Pharmacol. Sci. 28, 173-179.
• 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.
• 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.
• Dhami, G., K., Babwah, A. V., Sterne-Marr, R. and Ferguson, S. S. G. (2005) Phosphorylation-independent regulation of metabotropic glutamate receptor 1 signaling requires G protein-coupled receptor kinase 2 binding to the second intracellular loop. J. Biol. Chem. 280, 24420-24427.
• 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) β-Arrestin regulates a RalGDS-Ral effector pathway mediating cytoskeletal reorganization. Nat. Cell Biol. 4, 547-555.