Val J. Watts
Professor of Medicinal Chemistry and Molecular Pharmacology
Ph.D. - Pharmacology 1994 University of North Carolina (Dr. Richard B. Mailman)
Postdoc. - Molecular Pharmacology 1995-1998 Oregon Health Sciences University (Dr. Kim Neve)
The research in the Watts laboratory is designed to use a multi-disciplinary approach, combining molecular biology, biochemistry, and pharmacology to study the signaling mechanisms of G protein-coupled receptors (GPCRs) and the regulation of adenylyl cyclases. The fact that GPCRs are the target of more the 50% of today’s clinically used drugs emphasizes further the importance of these studies. Much of the work in his lab has focused on members of the dopamine, cannabinoid, 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 investigating their ability to modulate the activity of their primary effector, the enzyme adenylyl cyclase (AC). A second area of focus has included examining the effects of persistent Gαi/o-coupled receptor activation in vitro in order to understand and identify molecular changes following chronic drug exposure that may occur in vivo. Much of this work has focused on elucidating the mechanisms and pathways for D2 dopamine receptor-induced heterologous sensitization of adenylyl cyclase. Other exciting studies have used bimolecular fluorescence complementation (BiFC) to “visualize” and localize protein-protein interactions in living cells. BiFC is based on the complementation between fragments of fluorescent proteins that are fused to two interacting proteins. These fluorescent approaches and others are currently being used to study drug-modulated GPCR-AC, AC-AC, and AC-protein interactions in novel cellular models as well as in BiFC screening endeavors. More recent efforts have been focused on the development and execution of screening endeavors relevant to drug discovery and AC signaling. We have developed a number of new HTS assays for human and invertebrate GPCRs as well as individual AC isoforms that include using siRNA and small molecule libraries. We are currently exploring the ability of selective inhibitors of AC isoforms to serve as non-opioid alternatives for chronic pain, agents to treat opioid withdrawal, and for the treatment of alcohol use disorders (AUDs).
Doyle, T.B., Hayes, M.P., Chen, D.-H., Raskind, W.H., and Watts, V.J. Functional characterization of AC5 gain-of-function variants: Impact on the molecular basis of ADCY5-related dyskinesia. Biochem. Pharmacol. 163: 169-177, 2019 PMID: 3077269.
Baldwin, T.A., Li, Y., Brand, C.S., Watts, V.J., and Dessauer, C.W., Insights into the regulatory properties of adenylyl cyclase type 9. Mol. Pharmacol. 95: 349-360, 2019 PMID: 30696718.
Kaur, J., Soto-Velasquez, M., Ding, Z., Ghanbarpour, A., Lill, M.A., van Rijn, R.M., Watts, V.J., and Flaherty, D.P., Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain. Eur. J. Med. Chem. 162:568-585, 2019 PMID: 30472604.
Soto-Velasquez, M., Hayes, M. P., Alpsoy, A., Dykhuizen, E.C., and Watts, V.J. A novel CRISPR/Cas9-based cellular model to explore adenylyl cyclase and cyclic AMP signaling. Mol. Pharmacol. 94:963-972, 2018 PMID: 29950405
Hayes, M. P., Soto-Velasquez, M., Fowler, C.A., Watts, V.J.*, and Roman, D.L.* Identification of FDA-approved small molecules capable of disrupting the calmodulin-adenylyl cyclase 8 interaction through direct binding to calmodulin. ACS Chem. Neurosci. 9:346-357, 2018. *co-corresponding authors. PMID 28968502
Brust, T.F., Alongkronusmee, D. Soto-Velasquez, M., Baldwin, T.A., Ye, Z, Dai, M. Dessauer, C.W., van Rijn, R.M., and Watts, V.J., Identification of a selective small molecule inhibitor of type 1 adenylyl cyclase activity with analgesic properties. Sci. Signal.10: eaah5381, 2017 PMID: 28223412
Dessauer, C.W., Watts, V.J., Ostrom, R.S., Conti, M., Dove, S., and Seifert, R. International Union of Basic and Clinical Pharmacology: Structures and small molecule modulators of mammalian adenylyl cyclases. Pharmacol. Rev. 69:93-139, 2017 PMID: 28255005Nuss, A.B., Ejendal, F.K.F, Doyle, T.B., Meyer, J.M., Lang, E.G., Watts, V.J., and Hill, C.A., Dopamine Receptor Antagonists as New Mode-of-Action Insecticide Leads for Control of Aedes and Culex Mosquito Vectors. PLoS Neglected Trop. Diseases 9: e3515, 2015. PMID: 25793586
Conley, J.M., Meyer, J.M., Nuss, A.M., Doyle, T.B., Savinov, S.N., Hill, C.A., and Watts. V.J. Evaluation of AaDOP2 receptor antagonists reveals antidepressants and antipsychotics as novel lead molecules for control of the yellow fever mosquito, Aedes aegypti. J. Pharmacol. Exp. Therap. 352: 53-60, 2015. PMID: 25332454
Chemel, B.R., Bonner, L.A., Watts, V.J., Nichols, D.E. Ligand-specific roles for transmembrane 5 serine residues in the binding and efficacy of dopamine D1 receptor catechol agoinsts. Mol. Pharm. 81: 729-738, 2012. PMID: 22334593
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. PMID: 22292096
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. PMID: 20016021
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. PMID: 18524886
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. PMID: 18029912
Watts, V.J. Adenylyl cyclase isoforms as novel therapeutic targets: an exciting example of excitotoxicity neuroprotection. Mol. Inter. 7:70-73, 2007. (Invited Viewpoint) PMID: 17468386
Watts, V. J. and Neve K.A. Sensitization of adenylate cyclase by Galpha i/o-coupled receptors. Pharmacol. Ther., Invited Review 106:405-421, 2005. PMID: 15922020
Beazely, M.A., Alan, J.K., and Watts, V.J. Protein kinase C and epidermal growth factor stimulation of raf1 potentiates adenylyl cyclase type 6 activation in intact cells. Mol. Pharmacol. 67:250-259, 2005. PMID: 15470083
Vortherms, T.A., Nguyen, C.H., Berlot, C., and Watts, V.J. Using molecular tools to examine the role of Gas in sensitization of AC1. Mol. Pharmacol. 66:1617-1624, 2004. PMID: 15361543
Johnston, C.A., Beazely, M.A., Bilodeau, M.L., Andrisani, O., and Watts, V.J. Differentiation-induced alterations in cyclic AMP signaling in the Cath.A differentiated (CAD) neuronal cell line. J. Neurochem. 88:1497-1508, 2004. PMID: 15009651
Johnston, C.A., Beazely, M.A., Vancura, A.F., Wang, J.K.T., and Watts, V.J. Heterologous sensitization of adenylate cyclase is protein kinase A-dependent in Cath.a differentiated (CAD)-D2L cells. J. Neurochem. 82:1087-1096, 2002. PMID: 12358756
Watts, V.J. Molecular mechanisms for heterologous sensitization of adenylate cyclase. J. Pharmacol. Exp. Ther. 302:1-7, 2002. (Perspective in Pharmacology) PMID: 12065693