RT Journal Article
SR Electronic
T1 Agonist-Induced Sensitization of β-Adrenoceptor Signaling in Neonatal Rat Heart: Expression and Catalytic Activity of Adenylyl Cyclase
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 503
OP 510
VO 291
IS 2
A1 J. L. Zeiders
A1 F. J. Seidler
A1 T. A. Slotkin
YR 1999
UL http://jpet.aspetjournals.org/content/291/2/503.abstract
AB Agonist stimulation of neonatal cardiac β-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 Bmaxand 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 β-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. The American Society for Pharmacology and Experimental Therapeutics