Karen Gregory, Ph.D.
B.Sc. (Hons) Pharmacology, The University of Melbourne, 2004
Ph.D. Pharmacology, Monash University, 2009
Biosketch and Research Interests
Karen Gregory, Ph.D., is a postdoctoral research fellow who joined the Conn laboratory in August 2009. As a recipient of the prestigious Dowd Foundation (Neuroscience) and NHMRC (Australia) Dora Lush postgraduate research scholarships she undertook her doctoral training in the laboratories of Profs. Arthur Christopoulos and Patrick Sexton at Monash University in Melbourne, Australia. During her Ph.D., Karen investigated the functional consequences of allosteric modulation of M2 muscarinic acetylcholine receptors. Allosteric compounds bind to sites on receptors that are distinct from the endogenous ligand (orthosteric) binding site, and therefore offer much promise for the development of tools and/or therapeutics that show improved subtype selectivity compared to orthosteric compounds.
In the Conn laboratory, Karen continues to pursue her interest in G protein-coupled receptor (GPCR) pharmacology focusing on metabotropic glutamate receptor 5 (mGlu5). Activation of these receptors is being pursued as a novel therapeutic intervention for schizophrenia and cognitive disorders. Work in the Conn laboratory has identified numerous novel subtype-selective allosteric potentiators for these receptors, however, little is known about the location of the allosteric site(s) on these receptors. Karen aims to investigate the structural determinants that underlie allosteric ligand binding to mGlu5 with the aim to facilitate rational drug design efforts.
In addition, the receptor conformations engendered by allosteric ligands are likely to differ from those induced by orthosteric ligands. Thus it is possible that allosteric ligands may affect GPCR function in a manner that is different, and potentially more selective, compared to orthosteric ligands. With this in mind, Karen will assess the functional consequences of acute and chronic administration of existing and novel allosteric potentiators of mGlu5 in multiple indices of receptor function. Karen believes that subtype-selective allosteric modulators of mGlu5 will also provide necessary tools to better understand the physiological roles of these GPCRs.
A.S. HAMMOND, A.L. RODRIGUEZ, S.D. TOWNSEND, C.M. NISWENDER, K.J. GREGORY, C.W. LINDSLEY & P.J. CONN (2010) “Discovery of a novel chemical class of mGlu5 allosteric ligands with distinct modes of pharmacology” ACS Chem. Neurosci. Online publication date August 19th 2010.
K.J. GREGORY, E.N. DONG, J. MEILER & P.J. CONN (2010) “Allosteric Modulation of Metabotropic Glutamate Receptors: Structural Insights and Therapeutic Potential” Neuropharmacol. Online publication date July 14th 2010.
K.J. GREGORY, N.E. HALL, A.B. TOBIN, P.M. SEXTON & A CHRISTOPOULOS (2010) “Identification of orthosteric and allosteric site mutations in M2 muscarininc acetylcholine receptors that contribute to ligand-selective signaling bias” J. Biol. Chem. 285(10)7459-7474.
K.J. GREGORY, P.M. SEXTON & C.A. HICK (2010) “Second Messenger Assays for G Protein-Coupled Receptors” in Methods Express: G Protein-Coupled Receptors, Wiley-Blackwell, 31-52.
K.J. GREGORY, C VALANT, J SIMMS & A CHRISTOPOULOS (2009) “The Emergence of Allosteric Modulators for GPCRs” in “Shifting Paradigms in GPCRs” Wiley Press (in press).
C. VALANT. K.J. GREGORY, N.E. HALL, P.J. SCAMMELLS, M.J. LEW, P.M. SEXTON & A CHRISTOPOULOS (2008) “A Novel Mechanism of G Protein-Coupled Receptor Functional Selectivity: McN-A-343 as a Bitopic Orthosteric/Allosteric Ligand” J. Biol. Chem. 283(43)29312-21.
V.A. AVLANI*, K.J. GREGORY*, C.J. MORTON, M.W. PARKER, P.M. SEXTON & A CHRISTOPOULOS (2007) “Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands” J. Biol. Chem. 282(35):25677-86. (* these authors contributed equally to this work)
K.J. GREGORY, P.M. SEXTON & A. CHRISTOPOULOS (2007) “Allosteric Modulation of Muscarinic Acetylcholine Receptors” Curr. Neuropharm. 5:157-167.