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

Abstract

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 Gprotein-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. Regulation of ␤-Adrenoceptor Signaling in the Mature OrganismG-Protein-coupled receptors, one of the largest families of transmembrane signaling systems, are among the most studied mediators of cell-to-cell communication, pervading areas as diverse as central nervous system and peripheral autonomic function, cardiovascular and respiratory function, hormone actions, and carcinogenesis. This review will focus on the unusual features of receptor regulation during fetal and neonatal development, work that has largely involved the ␤-adrenoceptor (␤AR). In the adult, signaling through adenylyl cyclase (AC) via ␤-adrenoceptors has been particularly well characterized, representing a controlled, homeostatic system (Kohout and Lefkowitz, 2003). Ordinarily, excessive receptor stimulation is attenuated through two classes of mechanisms: uncoupling of ␤ARs from their response elements (desensitization) and reductions in the concentration of receptors at the cell membrane (down-regulation). Desensitization can be of two types, homologous and heterologous. With homologous desensitization, effects are restricted to ␤AR signaling, entailing phosphorylation of the agonistbound receptor on its carboxyl terminus, an effect mediated by the G-protein receptor kinases. Next, arrestins bind to the phosphorylated receptors, impairing receptor-G-protein interactions and thus terminating receptor signaling....

Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target?

“…Nevertheless, the AC response mediated by βARs, isoproterenol-stimulated AC activity, was unaffected or even increased, indicating that receptor binding is not the primary determinant of the receptor-mediated signaling response. These results reinforce the idea that the expression and function of signaling proteins downstream from the receptor provide the primary determinants of the net cellular response to receptor activation (Gao et al 1998(Gao et al , 1999Navarro et al 1991aNavarro et al , 1991bSlotkin et al 2001Slotkin et al , 2003. Accordingly, we evaluated AC responses mediated by direct stimulants, which test the inherent responsiveness of AC itself.…”

Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute β-adrenergic stimulation

“…Repeated agonist administration can cause desensitization of ␤-AR signaling in rat heart depending on the developmental stage of the animal (44). The dosing regimen for acute Iso treatment (1.25 mg/kg sc) was chosen carefully so that receptor desensitization did not occur.…”

“…The levels of PTEN were, however, not affected by the same treatment, suggesting a direct action of acute ␤-AR stimulation on PI3K signaling in postnatal hearts. During development, ␤-AR stimulation-induced receptor desensitization or downregulation is not present until 2 wk of age (3,44). The absence of ␤-AR desensitization in early development may be physiologically critical, as ␤-AR signaling is required for maintaining proper homeostasis and growth of the heart.…”

Effects of Prenatal Nicotine Exposure on Primate Brain Development and Attempted Amelioration with Supplemental Choline or Vitamin C: Neurotransmitter Receptors, Cell Signaling and Cell Development Biomarkers in Fetal Brain Regions of Rhesus Monkeys

“…Second, we focused on the effects on neurotransmitter receptors and cell signaling proteins that control the generation of the second messenger, cyclic AMP. In the developing brain, cyclic AMP plays a key role in the coordination of cell replication and differentiation, synaptic outgrowth, and apoptosis (Shaywitz and Greenberg, 1999;Stachowiak et al, 2003) and is a common site for disruption of brain development by neuroteratogens (Levitt et al, 1997;Slotkin et al, 2003a;Whitaker-Azmitia, 1991;Yanai et al, 2002). We performed a battery of tests designed to evaluate the impact of fetal nicotine exposure on the signaling cascade converging on adenylyl cyclase (AC) the enzyme that generates cyclic AMP (Figure 1).…”