Abstract
Acute activation of Gαi/o-coupled D2 dopamine receptors inhibits A2A adenosine receptor stimulation of adenylate cyclase. This antagonistic interaction between D2 dopamine and A2A adenosine receptors has been well documented; however, the effects of persistent activation of D2 dopamine receptors on subsequent A2A 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 D2L dopamine receptors on subsequent A2A adenosine receptor stimulation of adenylate cyclase in CAD-D2L and NS20Y-D2L neuroblastoma cells. Short- and long-term activation of D2L dopamine receptors markedly increased 5′-N-methylcarboxamidoadenosine (MECA)-stimulated cyclic AMP accumulation 1.4-fold and 1.7-fold, respectively. D2L receptor-induced sensitization of A2A-stimulated cyclic AMP accumulation was blocked by the D2 antagonist spiperone and pertussis toxin pretreatment. In addition, persistent activation of A2A adenosine receptors resulted in 50% desensitization of subsequent MECA-stimulated cyclic AMP accumulation; however, MECA-induced desensitization of A2A adenosine receptors did not prevent completely quinpirole-induced sensitization of adenylate cyclase. These studies revealed a novel mode of regulation between D2L dopamine and A2A adenosine receptors and suggest a cooperative interaction in the regulation of cyclic AMP signaling.
Footnotes
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This work was supported by a Purdue Research Foundation grant (to T.A.V. and V.J.W.) and National Institute of Mental Health Grant MH60397 (to V.J.W.).
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DOI: 10.1124/jpet.103.057083.
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ABBREVIATIONS: AC(1-9), adenylate cyclase type (1-9); CAD, Cath.a. differentiated cells; DARPP-32, dopamine- and cyclic AMP-regulated phosphoprotein 32 kDa; EBSS, Earle's balanced salt solution; ANOVA, analysis of variance; PKA, cyclic AMP dependent protein kinase A.
- Received July 16, 2003.
- Accepted September 17, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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