Agonist-induced sensitization of beta-adrenoceptor signaling in neonatal rat heart: Expression and catalytic activity of adenylyl cyclase

Agonist stimulation of neonatal cardiac beta-adrenoceptors produces heterol ogous sensitization of adenylyl cyclase (AC) signaling, rather than desensi tization, as seen in adults. We examined the ontogenetic patterns of AC exp ression and activity, and evaluated isoproterenol effects on this pattern. [H-3]Forskolin binding showed an increase in AC concentration across the pe riod (birth to 25 days of age) in which agonist-induced sensitization is re placed by desensitization; binding affinity also increased, suggesting a sh ift in conformation and/or isoform. Indeed, catalytic properties of AC chan ged substantially with development, as evaluated by AC responses to forskol in versus Mn2+. In contrast, there were only minor changes in the levels of mRNAs encoding the two major isoforms. Neonates given repeated isoproteren ol treatment showed an enhancement of [H-3]forskolin binding B-max and a pr ecocious shift to the mature affinity state and corresponding catalytic pro perties. Although isoproterenol caused significant increases in AC mRNAs, t he effects were small and showed no isoform preference. Thus, a primary mod e for ontogenetic increases in cardiac cellular responsiveness to adrenergi c stimulation is the increase in AC activity attendant upon an absolute inc rease in the membrane concentration of AC molecules, along with changes in the catalytic properties of AC. The lack of correlation between mRNA and AC protein suggests that the primary regulatory events are post-transcription al. The induction of AC by beta-adrenoceptor stimulation in the fetus and n eonate accounts for heterologous, agonist-induced sensitization, a phenomen on that preserves cellular responses during the period of the perinatal tra nsition.