Beta-adrenoceptor signaling in the developing brain: sensitization or desensitization in response to terbutaline.
Beta(2)-adrenoceptor agonists are commonly used to arrest preterm labor but they also penetrate the placenta to stimulate fetal beta-adrenergic receptors (betaAR), and have been implicated in subsequent neurobehavioral deficits. We administered terbutaline to pregnant rats on gestational days (GD) 17-20 and during two postnatal (PN) periods, PN2-5 and PN11-14, that correspond to third trimester human neurological development. We then examined betaAR binding sites and adenylyl cyclase (AC) signaling in fetal brain or neonatal brain regions. Although fetal terbutaline administration evoked betaAR downregulation, the ability of isoproterenol to stimulate AC was enhanced instead of desensitized. Sensitization occurred at post-receptor signaling proteins, as augmented responses were also seen for stimulants that bypass the receptors to work on G-proteins (NaF) or that stimulate AC directly (forskolin and Mn(2+)). When terbutaline was given on PN2-5, betaAR downregulation was obtained in brainstem, forebrain and cerebellum, but desensitization of the AC response was seen only in the forebrain; the desensitization was heterologous, reflecting decrements in total AC activity rather than specific loss of the betaAR response. With treatment on PN11-14, only the cerebellum showed betaAR downregulation and induction at the level of post-receptor signaling proteins maintained the betaAR-mediated AC response. Our results indicate that, unlike the adult, betaAR signaling in the fetus and neonate is resistant to homologous desensitization by beta-agonists, and in fact, displays heterologous sensitization that sustains or enhances the overall response. The inability to desensitize betaAR responses may lead to disruption of neural cell development as a consequence of tocolytic therapy.
Slotkin
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TA
Box 3813 DUMC, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Tate
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CA
Cousins
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MM
Seidler
F J
FJ
D000222:Adaptation, Physiological / Q000187:drug effects; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013726:Terbutaline / Q000494:pharmacology*; D015149:Tocolytic Agents / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D015149:Tocolytic Agents; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D013726:Terbutaline