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NEUROPHARMACOLOGY

Sensitization of Neuronal A_2A Adenosine Receptors after Persistent D₂ Dopamine Receptor Activation

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana

Acute activation of G_i/o-coupled D₂ dopamine receptors inhibits A_2A adenosine receptor stimulation of adenylate cyclase. This antagonistic interaction between D₂ dopamine and A_2A adenosine receptors has been well documented; however, the effects of persistent activation of D₂ dopamine receptors on subsequent A_2A adenosine receptor signaling have not been explored. The present study investigated the effects of short-term (3-h) and long-term (18-h) activation of D_2L dopamine receptors on subsequent A_2A adenosine receptor stimulation of adenylate cyclase in CAD-D_2L and NS20Y-D_2L neuroblastoma cells. Short- and long-term activation of D_2L dopamine receptors markedly increased 5'-N-methylcarboxamidoadenosine (MECA)-stimulated cyclic AMP accumulation 1.4-fold and 1.7-fold, respectively. D_2L receptor-induced sensitization of A_2A-stimulated cyclic AMP accumulation was blocked by the D₂ antagonist spiperone and pertussis toxin pretreatment. In addition, persistent activation of A_2A adenosine receptors resulted in 50% desensitization of subsequent MECA-stimulated cyclic AMP accumulation; however, MECA-induced desensitization of A_2A adenosine receptors did not prevent completely quinpirole-induced sensitization of adenylate cyclase. These studies revealed a novel mode of regulation between D_2L dopamine and A_2A adenosine receptors and suggest a cooperative interaction in the regulation of cyclic AMP signaling.

Address correspondence to: Dr. Val J. Watts, Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Dr., RHPH 224A, West Lafayette, IN 47907. E-mail: wattsv{at}pharmacy.purdue.edu

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				P.-A. Vidi, B. R. Chemel, C.-D. Hu, and V. J. Watts Ligand-Dependent Oligomerization of Dopamine D2 and Adenosine A2A Receptors in Living Neuronal Cells Mol. Pharmacol., September 1, 2008; 74(3): 544 - 551. [Abstract] [Full Text] [PDF]

				T. A. Vortherms, C. H. Nguyen, C. H. Berlot, and V. J. Watts Using Molecular Tools to Dissect the Role of G{alpha}s in Sensitization of AC1 Mol. Pharmacol., December 1, 2004; 66(6): 1617 - 1624. [Abstract] [Full Text] [PDF]