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Vol. 291, Issue 2, 503-510, November 1999
-Adrenoceptor Signaling in
Neonatal Rat Heart: Expression and Catalytic Activity of Adenylyl
Cyclase1
Department of Pharmacology and Cancer Biology, Duke University
Medical Center, Durham, North Carolina
Agonist stimulation of neonatal cardiac 
-adrenoceptors produces
heterologous sensitization of adenylyl cyclase (AC) signaling, rather
than desensitization, as seen in adults. We examined the ontogenetic
patterns of AC expression and activity, and evaluated isoproterenol
effects on this pattern. [3H]Forskolin binding showed an
increase in AC concentration across the period (birth to 25 days of
age) in which agonist-induced sensitization is replaced by
desensitization; binding affinity also increased, suggesting a shift in
conformation and/or isoform. Indeed, catalytic properties of AC changed
substantially with development, as evaluated by AC responses to
forskolin versus Mn2+. In contrast, there were only minor
changes in the levels of mRNAs encoding the two major isoforms.
Neonates given repeated isoproterenol treatment showed an enhancement
of [3H]forskolin binding Bmax
and a precocious shift to the mature affinity state and corresponding
catalytic properties. Although isoproterenol caused significant
increases in AC mRNAs, the effects were small and showed no isoform
preference. Thus, a primary mode for ontogenetic increases in cardiac
cellular responsiveness to adrenergic stimulation is the increase in AC
activity attendant upon an absolute increase 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-transcriptional.
The induction of AC by -adrenoceptor stimulation in the fetus and
neonate accounts for heterologous, agonist-induced sensitization, a
phenomenon that preserves cellular responses during the period of the
perinatal transition.
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