Atypical regulation of hepatic adenylyl cyclase and adrenergic receptors during a critical developmental period: agonists evoke supersensitivity accompanied by failure of receptor down-regulation.
Ordinarily, beta-adrenergic receptors and responses linked to the receptors increase with development but in the liver, beta-receptors are higher in the fetus and neonate than in adulthood. We examined how hepatic beta-receptor signaling mediated through adenylyl cyclase is regulated in rats of different ages. In each case, animals were pretreated with isoproterenol for 4 d, and on the 5th d, hepatic membrane preparations were examined for adenylyl cyclase activity and receptor binding capabilities. Uniquely in 6-d-old animals, the cyclase response to isoproterenol was enhanced by chronic pretreatment, caused by heterologous sensitization mediated through effects on total catalytic activity (increased response to forskolin-Mn2+) and on G-protein coupling (enhanced effect of fluoride and increased GTP dependence of basal activity). Isoproterenol pretreatment failed to cause beta-receptor down-regulation in 6-d-old animals, but by 15 d of age, down-regulation was detected along with slight desensitization of the cyclase response. However, at 25 d, neither effect was present. In adulthood, repeated isoproterenol administration failed to cause cyclase desensitization but did reduce beta-receptor numbers; the loss of receptors was still unusual in that beta-receptor down-regulation could be achieved with either isoproterenol or with methoxamine, an alpha-receptor agonist. The results indicate that, early in development, hepatic beta-receptor-mediated responses are enhanced, not desensitized, after chronic stimulation. These effects would foster responsiveness of hepatic gluconeogenesis in the face of the massive adrenergic stimulation associated with the transition from fetal to neonatal life. In adulthood, when receptor numbers are far lower than in the neonate, the inability to desensitize the signaling cascade despite receptor down-regulation would serve to maintain the response to catecholamines.
Thai
L
L
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Galluzzo
J M
JM
McCook
E C
EC
Seidler
F J
FJ
Slotkin
T A
TA
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000375:Aging / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation; D005260:Female; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases; D007545:Isoproterenol