Anomalous regulation of beta-adrenoceptor signaling in brain regions of the newborn rat.
Desensitization, an essential homeostatic response to excessive or continued beta-adrenoceptor (betaAR) stimulation, is deficient in immature cells. To determine the mechanisms underlying anomalous betaAR responses in newborn rats, we administered terbutaline, a beta2AR agonist, on postnatal day 2 and evaluated signaling through adenylyl cyclase (AC) in cell membrane preparations 4 h later. Although a small decrement in isoproterenol-stimulated AC was obtained in the forebrain, robust sensitization was seen in the brainstem and cerebellum, in association with heterologous increases in AC catalytic activity: increased basal, dopamine-stimulated and forskolin-stimulated AC. Superimposed on this global increase, there was a small degree of betaAR and dopamine receptor desensitization, characterized by decreases in the isoproterenol/forskolin and dopamine/forskolin AC activity ratios. Our results indicate that, in some immature brain regions, betaAR desensitization is masked by more substantial increases in the activity of signaling elements downstream from the receptors, resulting in sustained responses in the face of continued receptor stimulation. These effects are likely responsible for the maintenance of betaAR activity associated with neurotrophic input during synaptogenesis but may also contribute to adverse effects of betaAR agonists used in preterm labor.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Duke Univ. Med. Ctr., Durham, NC 27710, USA. t.slotkin@duke.edu
Theodore A
TA
Slotkin
Frederic J
FJ
Seidler
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013726:Terbutaline / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases; D013726:Terbutaline