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 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. [(3)H]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 Mn(2+). 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 [(3)H]forskolin binding B(max) 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 beta-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.
Zeiders
J L
JL
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Seidler
F J
FJ
Slotkin
T A
TA
D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001965:Bromides / Q000633:toxicity; D005576:Colforsin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000493:pharmacokinetics*; D008297:Male; D008345:Manganese / Q000494:pharmacology; D016627:Oxidopamine / Q000633:toxicity; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013562:Sympathectomy; D013566:Sympathomimetics / Q000494:pharmacology*; D014158:Transcription, Genetic
D001965:Bromides; D020033:Protein Isoforms; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D013566:Sympathomimetics; D005576:Colforsin; D008345:Manganese; D016627:Oxidopamine; D000262:Adenylyl Cyclases; D007545:Isoproterenol