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Vol. 297, Issue 3, 1201-1209, June 2001

Heterologous Sensitization of Recombinant Adenylate Cyclases by Activation of D2 Dopamine Receptors

Medhane G. Cumbay and Val J. Watts

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

Persistent activation of Galpha i/o-coupled receptors results in an enhanced responsiveness of drug-stimulated adenylate cyclase activity through an unknown mechanism. This agonist-induced heterologous sensitization of drug-stimulated cyclic AMP accumulation has been proposed to be a mechanism by which cells adapt to prolonged Galpha i/o activation. Heterologous sensitization was examined in human embryonic kidney 293 cells stably expressing D2L dopamine receptors in combination with recombinant isoforms of adenylate cyclase. The ability of each isoform to be differentially regulated by G protein subunits and other signaling intermediates allowed us to identify potential mechanisms that are involved in heterologous sensitization of adenylate cyclase. We now report that both short- and long-term activation of D2L dopamine receptors resulted in a marked degree of sensitization of ACI, ACII, ACV, and ACIX, but not ACVIII. The effects of agonist treatment on ACI, ACII, and ACVIII appeared to be dependent upon the ability of these adenylate cyclase isoforms to synergistically respond to selective activators in the presence of activated Galpha s. Sensitization of ACV was characterized by enhanced cyclic AMP accumulation following Galpha s or forskolin stimulation. Furthermore, agonist pretreatment enhanced the basal levels of cyclic AMP accumulation in ACV/D2L cells, an effect that was not observed with the other adenylate cyclase isoforms. ACIX, which has no known activators other than Galpha s, showed robust agonist-induced sensitization of isoproterenol-stimulated cyclic AMP accumulation. In summary, heterologous sensitization appeared to be related to the ability of each adenylate cyclase isoform to be modulated by Galpha s.

0022-3565/01/2973-1201$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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