Department of Medicinal Chemistry and Molecular Pharmacology Personnel - Val J. Watts
Specialization: Molecular Pharmacology
EducationB.S. - Pharmacy 1990 Ohio Northern University
Ph.D. - Pharmacology 1994 University of North Carolina (Dr. Richard B. Mailman)
Postdoc. - Molecular Pharmacology 1995-1998 Oregon Health Sciences University (Dr. Kim Neve)
Research: Molecular Pharmacology
The research in the Watts laboratory is designed to use a multi-disciplinary approach, combining molecular biology, pharmacology, and biochemistry, to study the pharmacology and signaling mechanisms of G protein-coupled receptors (GPCRs). The fact that GPCRs are the target of approximately 50% of today’s clinically used drugs emphasizes further the relevance of these studies. Much of the work in his lab has focused on members of the dopamine, serotonin, and adenosine receptor families. Studies have examined the pharmacology of these receptors including the characterization of novel ligands that activate these receptors as well as examining the receptors’ ability to modulate the activity of their primary effector, the enzyme adenylyl cyclase.
A major area of focus is the study of the effects of sub-acute and chronic receptor activation on GPCR interactions, G protein signaling, and adenylyl cyclase activity in vitro (using cultured cell lines and primary neuronal cultures) and in vivo (genetic mouse models and Syrian hamsters), in order to understand and identify molecular changes following chronic drug exposure that may occur in vivo. For example, persistent activation of inhibitory receptors results in the sensitization of several isoforms of adenylyl cyclase to subsequent stimulation. This heterologous sensitization has been proposed to be one mechanism by which a cell adapts to prolonged inhibition of cyclic AMP synthesis, and may be a cellular model of drug tolerance and dependence. Understanding the drug-induced biochemical changes and the mechanisms for these changes may help us to better understand a number of clinical observations. Two additional areas of interest include drug discovery efforts for the identification of modulators of adenylyl cyclase isoforms and the molecular characterization of ligands (i.e. agonists and allosteric modulators) for the treatment of hypodopaminergic disorders, such as Parkinson’s Disease and cognitive deficits associated with schizophrenia.
More recent efforts have been aimed at examining the potential role of receptor oligomerization in agonist-directed trafficking and cellular signaling. For example, several studies have provided evidence that prolonged dopamine receptor activation can modulate the signaling pathways of the CB1 cannabinoid receptor (the target of the active ingredient in marijuana) and the A2A adenosine receptor (the target of caffeine). One mechanism for dopamine modulation of these important receptors may involve receptor oligomerization. In an effort to explore this possibility, we established bimolecular fluorescence complementation (BiFC) and BiFC-FRET as tools to directly visualize dopamine receptor homo- and heteromer formation with adenosine and cannabinoid receptors. Recent data suggests that A2A-D2 and CB1-D2 heterodimer formation is influenced by prolonged exposure to receptor ligands. These observations may help in understanding pathological situations resulting from chronic drug treatments.
A second new arena of discovery involves a drug discovery effort in the area of insecticides. These studies are carried in collaboration with Dr. Catherine Hill (Entomology) in the College of Agriculture. The Hill lab has identified more than 100 different GPCRs in the genomes of the Aedes aegypti mosquito vector of dengue and yellow fever, the Anopheles gambiae mosquito vector of malaria, the Culex quinquefasciatus mosquito vector of filariasis and encephalitis, and the Ixodes scapularis tick vector of Lyme disease. These studies have provided a basis for the functional characterization of GPCRs and their prioritization as potential subjects for insecticide development. Due to their presumed significance in insect neurobiology, biogenic amine (e.g. dopamine, tyramine, and serotonin) receptors are highly attractive candidates to explore as new targets for chemical control. Our lab has been engaged in the pharmacological characterization and HTS assay development of several dopamine and tyramine receptors.
In summary, the goals of Dr. Watts’ research are to provide important information describing the biochemical changes associated with both short- and long-term activation of GPCRs and to identify novel novel receptor ligands and signaling pathways. This effort is encouraged by the molecular discovery and identification of uniquely regulated signaling effectors (e.g. multiple isoforms of adenylyl cyclase and novel GPCRs) as well as the role of biogenic amine receptors in human health.
Position Open: Postdoctoral Fellowship in Molecular Pharmacology, the candidate should have expertise in molecular biology relevant to the study of the cellular biology of G protein-coupled receptors and their effectors. The position is in a newly-renovated active laboratory with a focus on dopamine receptor signaling including activation mechanisms, G protein modulation, and adenylyl cyclase signaling using novel cellular models. Newer initiatives also being developed include small molecule library screening, fluorescent microscopy, and BiFC.
Lab Members:Jason Michael Conley (Graduate Student)
Trevor Burgess Doyle (Graduate Student)
Karin F. K. (Kaisa) Ejendal (Postdoctoral Research Associate)
Monica P. Soto Velasquez (MCMP Instrument TA)
Conley, J.M., Brand, C.S., Bogard, A.S., Pratt, E.P.S., Xu, R., Hockerman, G.H., Ostrom, R., Dessauer, C.W., and Watts, V.J., Development of a high-throughput screening paradigm for the discovery of small molecule modulators of adenylyl cyclase: Identification of an adenylyl cyclase 2 inhibitor. J. Pharmacol. Exp. Therap. 347: 276-287, 2013.
Conley, J.M. and Watts, V.J. Differential effects of AGS3 expression on D2L dopamine receptor-mediated adenylyl cyclase signaling. Cell. Mol. Neurobiol. 33: 551-558, 2013.
Ejendal, K.F.K., Dessauer, C.W., Hebert, T. E., and Watts, V.J., Dopamine D2 receptor-mediated heterologous sensitization of AC5 requires signalosome assembly. J. Sig. Trans.2012: Article ID 210324, 2012.
Meyer, J.M., Ejendal, K.F.K., Avramova. L., Garland-Kuntz, E., Giraldo-Calderón, G., Brust, T.F, Watts, V.J. and Hill, C.A., A “genome-to-lead” approach for insecticide discovery: pharmacological characterization and chemical compound screening of Aedes aegypti D1-like dopamine receptors. PLoS Neglected Trop. Diseases. 6: e1478, 2012.
McCorvy, J.D., Watts, V.J., and Nichols, D.E., Comparison of the D1 dopamine full agonists, dihydrexidine and doxanthrine, in the 6-OHDA rat model of Parkinson’s disease. Psychopharmacology. Psychopharmacology. 222:81-87, 2012.
Cueva, J.P., Gallardo-Godoy, A., Juncosa, J.I., Vidi, P.A., Lill, M.A., Watts, V.J., and Nichols, D.E., Probing the steric space at the floor of the D1 dopamine receptor orthosteric binding domain: 7α-, 7β-, 8α-, and 8β-methyl substituted dihydrexidine analogues. J. Med. Chem. 54: 5508-5521, 2011.
Vidi, P.A., Ejendal, K.F.K., Przybyla, J.A., and Watts, V.J., Fluorescent protein complementation assays: new tools to study G protein-coupled receptor oligomerization and GPCR-mediated signaling. Mol. Cell. Endocrinol., 331:185-193, 2011.
Przybyla, J.A. and Watts, V.J., Ligand-induced regulation and localization of cannabinoid CB1 and dopamine D2 receptor heterodimers. J. Pharmacol. Exp. Therap., 332:710-719, 2010.
Przybyla, J.A., Chemel, B.R., Hsu, K.J., Riese, D.J., McCorvy, J. D., Chester, J.A., Nichols, D.E., and Watts, V.J., Comparison of the enantiomers of (±)-doxanthrine, a high efficacy full dopamine D1 receptor agonist, and a reversal of enantioselectivity at D1 versus alpha2C adrenergic receptors. Eur. J. Neuropsychopharmacol. 19:138-146, 2009.
Vidi, P.A., Chemel, B.R., Hu, C.-D., and Watts, V.J., Ligand-dependant oligomerization of dopamine D2 and adenosine A2A receptors in living neuronal cells. Mol. Pharmacol. 74:544-551, 2008.
Chester, J.A. and Watts, V.J., Adenylyl Cyclase 5: A New Clue in the Search for the "Fountain of Youth"? Sci STKE. 2007: pe64, 2007.
This record was last updated on Jan 8, 2016 at 10:42 AM