Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling.
In the fetus and neonate, beta-adrenoceptor stimulation fails to produce physiological desensitization. The current study explores the mechanisms underlying the response pattern in neonatal rats. Homologous cardiac beta-adrenergic desensitization caused by isoproterenol treatment in vivo was demonstrable in adult rats by the immediate (2h) and specific loss of the ability of isoproterenol, but not glucagon, to stimulate adenylyl cyclase in vitro. Homologous desensitization was absent when the same treatment was given to neonates. By 12 h post-treatment, the adults showed heterologous desensitization (loss of the response to glucagon), an effect which was once again absent in the immature rats. The absence of desensitization in neonates did not reflect a deficiency in the activity or subcellular distribution of beta ARK1, the enzyme that initiates the phosphorylation and consequent desensitization of beta-adrenoceptors. On the other hand, neonates showed relatively poor receptor-Gs transduction as assessed by the GTP-induced shift in receptor ligand binding. Repeated isoproterenol treatment of adult rats led to uncoupling of receptor-G-protein transduction but the same treatment in neonates enhanced transduction. Furthermore, neonatal sympathectomy with 6-OHDA interfered with the ontogenetic rise in beta-adrenoceptor-Gs interactions. These results indicate that the maintenance of agonist responses in the face of neonatal adrenergic stimulation does not reflect simply an absence of the ability to elicit homologous or heterologous desensitization but rather represents an active regulatory mechanism in which neural input exerts a positive trophic role at the level of G-protein function.
Zeiders
J L
JL
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Seidler
F J
FJ
Iaccarino
G
G
Koch
W J
WJ
Slotkin
T A
TA
D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007545:Isoproterenol / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D007545:Isoproterenol