Heterologous sensitization of recombinant adenylate cyclases by activationof D-2 dopamine receptors

Persistent activation of G alpha (i/o)-coupled receptors results in an enha nced responsiveness of drug-stimulated adenylate cyclase activity through a n unknown mechanism. This agonist-induced heterologous sensitization of dru g-stimulated cyclic AMP accumulation has been proposed to be a mechanism by which cells adapt to prolonged G alpha (i/o) activation. Heterologous sens itization was examined in human embryonic kidney 293 cells stably expressin g D-2L dopamine receptors in combination with recombinant isoforms of adeny late cyclase. The ability of each isoform to be differentially regulated by G protein subunits and other signaling intermediates allowed us to identif y potential mechanisms that are involved in heterologous sensitization of a denylate cyclase. We now report that both short- and long-term activation o f D-2L dopamine receptors resulted in a marked degree of sensitization of A CI, ACII, ACV, and ACIX, but not ACVIII. The effects of agonist treatment o n ACI, ACII, and ACVIII appeared to be dependent upon the ability of these adenylate cyclase isoforms to synergistically respond to selective activato rs in the presence of activated G alpha (s). Sensitization of ACV was chara cterized by enhanced cyclic AMP accumulation following G alpha (s) or forsk olin stimulation. Furthermore, agonist pretreatment enhanced the basal leve ls of cyclic AMP accumulation in ACV/D-2L cells, an effect that was not obs erved with the other adenylate cyclase isoforms. ACIX, which has no known a ctivators other than G alpha (s), showed robust agonist-induced sensitizati on of isoproterenol-stimulated cyclic AMP accumulation. In summary, heterol ogous sensitization appeared to be related to the ability of each adenylate cyclase isoform to be modulated by G alpha (s).