Val J. Watts, Ph.D. Associate Dean for Research Associate Professor of Medicinal Chemistry and Molecular Pharmacology Phone: (765) 496-3872 Fax: (765) 494-1414 E-mail: wattsv@purdue.edu Personal webpage: http://people.pharmacy.purdue.edu/~vwatts/ Full directory listing

Specialization: Molecular Pharmacology

Education

Research: Molecular Pharmacology

The research in our laboratory is designed to use a multi-disciplinary approach, combining molecular biology, biochemistry, and pharmacology to study the signaling properties of G protein-coupled receptors with an emphasis on dopamine receptor systems. Dopamine receptors are of particular interest because they have been implicated in a variety of neurological disorders including schizophrenia, depression, Tourette's syndrome, Parkinson's disease, and drug abuse. In addition to dopamine receptors, we have experience with several other GPCRs including serotonin, adrenergic, cannabinoid, adenosine, and glucagon-like peptide 1 receptors. One of the primary effects of GPCR activation is modulation of the enzyme adenylyl cyclase. There are nine membrane-bound isoforms of the enzyme adenylyl cyclase (AC1-AC9) and each has a unique pattern of GPCR regulation. We are currently developing new technologies to study receptor-specific regulation of adenylyl cyclases.

One long standing interest of our laboratory is the study of the effects of persistent receptor activation in vitro in order to understand and identify molecular changes following chronic drug exposure that may occur in vivo. One consequence of repeated ingestion of many drugs of abuse (i.e. cocaine, amphetamine), many therapeutic agents (i.e. antidepressants, anti-Parkinson's agents), and appetitive behaviors (sexual experience, gambling) is a resulting increase of synaptic dopamine capable of activating dopamine receptors. We have shown that persistent activation of D2-like dopamine receptors leads to heterologous sensitization of adenylyl cyclases in a number of cultured cell lines and more recently in two animal models. Heterologous sensitization of adenylyl cyclase is characterized by an enhanced response to drug-stimulated cyclic AMP accumulation following agonist pretreatment. Understanding the biochemical changes following repeated/prolonged dopamine receptor activation may help us to understand the changes that occur in clinical settings.

More recent studies have also 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 have now established bimolecular fluorescence complementation (BiFC) as a tool to directly visualize dopamine receptor homo- and heteromer formation with adenosine and cannabinoid receptors. Recent data suggest that dopamine D2-adenosine A2A heteromer formation is influenced by prolonged exposure to D2 or A2A ligands. These observations may help in understanding pathological situations resulting from chronic drug treatments.

In summary, the goals of our research are to provide important information describing the biochemical changes associated with both short- and long-term activation of GPCRs and to identify novel signaling pathways of dopamine receptors. This effort is encouraged by uniquely regulated signaling effectors (e.g. multiple isoforms of adenylyl cyclase) as well as interacting partners of the dopamine receptor family.

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.

Click here for PubMed Publications or see below:

Representative Publications

Vidi, P.A. and Watts, V.J. Protein-fragment complementation biosensors in the study of G protein-coupled receptor oligomerization and signaling. Mol. Pharmacol. 75: 733-739, 2009.

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., Chen, J., Irudayaraj, J.M.K., and Watts, V.J., Adenosine A2A Receptors Assemble into Higher-order Oligomers at the Plasma Membrane. FEBS Letters 582: 3985-3990, 2008.

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.

Watts, V.J. Adenylyl cyclase isoforms as novel therapeutic targets: an exciting example of excitotoxicity neuroprotection. Mol. Inter. 7: 70-73, 2007.

Chester, J.A. and Watts, V.J. Adenylyl Cyclase 5: A New Clue in the Search for the "Fountain of Youth"?. Sci STKE. pe64, 2007.

Chester, J.A., Mullins, A.J., Nguyen, C.H., Watts, V.J., and Meisel, R.L. Repeated quinpirole treatments produce neurochemical sensitization and associated behavioral changes in female hamsters . Psychopharmacology 188: 53-62, 2006.

Nguyen, C.H. and Watts, V.J. Dexamethasone-induced Ras protein 1 negatively regulates protein kinase Cδ: Implications for adenylyl cyclase 2 signaling. Mol. Pharmacol. 69:1763-1771, 2006.

Beazely, M.A. and Watts, V.J. Regulatory properties of adenylate cyclases type 5 and 6: A progress report. Eur. J. Pharmacol., Invited Review 535: 1-12, 2006.

Vortherms, T.A., Nguyen, C.H., Bastepe, M., Juppner, H., and Watts, V.J. D₂ dopamine receptor-induced sensitization of adenylyl cyclase type 1 is Gα_s independent. Neuropharmacology 50:576-584, 2006.