Extracellular cAMP inhibits D(1) dopamine receptor expression in CAD catecholaminergic cells via A(2a) adenosine receptors.

摘要

The expression of D(1) dopamine (DA) receptor gene is regulated during development, aging, and pathophysiology. The extracellular factors and signaling mechanisms that modulate the expression of D(1) DA receptor have not been well characterized. Here, we present novel evidence that endogenous D(1) DA receptor expression is inhibited by extracellular cAMP in the Cath.A Derived (CAD) catecholaminergic neuronal cell line. CAD cells express the multi-drug resistance protein 5 transporters and secrete cAMP. Addition of exogenous cAMP decreases D(1) receptor mRNA and protein greater than fourfold in 24 h. The cAMP-induced decrease of D(1) receptor mRNA levels is blocked by cGMP and by 1,3-dipropyl-8-(p-sulfo-phenyl)xanthine, an inhibitor of ecto-phosphodiestrase. Extracellular AMP, a metabolite of cAMP, also independently decreased D(1) receptor mRNA levels. Inhibitors of ecto-nucleotidases, alpha,beta-methyleneadenosine 5'-di-phosphate and GMP, completely blocked the decrease of D(1) receptor mRNA by extracellular cAMP, but only partially blocked the decrease induced by extracellular AMP. Levamisole, an inhibitor of tissue non-specific alkaline phosphatase, completely blocked the AMP-induced decrease of D(1) receptor mRNA. The extracellular cAMP, AMP, and adenosine (ADO)-induced decrease in D(1) receptor mRNA expression are mediated by A(2a) ADO receptor subtype. The results suggest a novel molecular mechanism linking activation of A(2a) ADO receptors with inhibition of D(1) DA receptor expression.