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PERSPECTIVES IN PHARMACOLOGY

Ontogenesis of -Adrenoceptor Signaling: Implications for Perinatal Physiology and for Fetal Effects of Tocolytic Drugs

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina

G-Protein-coupled receptors play an instrumental role in cellular development and function. In the mature organism, receptor signaling is controlled through the processes of desensitization and down-regulation. Recent evidence suggests that these regulatory mechanisms are not inherent properties, however, but rather are acquired during ontogenesis. This review focuses on -adrenoceptors (ARs), which are found in fetal and neonatal tissues and are effectively linked through adenylyl cyclase (AC) to the production of cAMP. Agonist-induced stimulation of ARs in the immature organism fails to produce desensitization, and instead, responsiveness increases. The unique mechanisms underlying this anomalous response involve induction of AC, a switch to more catalytically efficient AC isoforms, an increase in the ratio of stimulatory to inhibitory G-proteins, and interference with the expression and/or function of other G-protein-linked receptors that provide offsetting, inhibitory inputs. These adjustments are thus heterologous, influencing signaling mediated by a host of other G-protein-coupled neurotransmitter and hormone receptors. The net effect is to maintain and augment AR signaling in the face of continued stimulation, properties that disappear with maturation. The unique regulatory mechanisms for AR signaling in the fetus and neonate provide the necessary physiological adjustments required for the perinatal transition from intrauterine to extrauterine life. At the same time, however, the inability to restrict AR function may underlie adverse effects of AR-agonist tocolytics that are used in the treatment of preterm labor.

Address correspondence to: Dr. Theodore A. Slotkin, Dept. of Pharmacology and Cancer Biology, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710. E-mail t.slotkin{at}duke.edu

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