Ontogeny of β-adrenoceptor/adenylyl cyclase desensitization mechanisms: the role of neonatal innervation

Slotkin, Theodore A.; Saleh, J. L.; Zhang, J; Seidler, Frederic J.

doi:10.1016/s0006-8993(96)00978-x

Cited by 16 publications

(17 citation statements)

References 31 publications

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“…Because the timing of the transition coincides with the development of innervation, it is tempting to speculate that neural input itself is responsible for initiating the maturational changes that convert the neonatal pattern to that of the adult. Nevertheless, neither neonatal denervation nor treatments that reduce neural input to ␤AR targets prevents the loss of the unique neonatal response, although they do modulate the timing of the shift (Slotkin et al, 1996). Accordingly, the transition from sensitization to desensitization may be an autochthonous property of cell differentiation.…”

Section: Ontogenesis Of ␤-Adrenoceptormentioning

confidence: 99%

“…In the adult, ␤AR blockade or the destruction of neuronal inputs to ␤ARs result in compensatory supersensitivity of receptor signaling and eventually to up-regulation of the number of receptors on the cell surface (Kohout and Lefkowitz, 2003). When these events are triggered in the developing organism, however, there is little or no increase in sensitivity or receptor numbers (Slotkin et al, 1996;Garofolo et al, 2002). Interestingly, the receptors then never acquire some of their essential properties.…”

Section: Neural Input and The Programming Of Future Cellular Responsimentioning

confidence: 99%

“…Interestingly, the receptors then never acquire some of their essential properties. For example, neonatal denervation of the heart with the neurotoxin 6-hydroxydopamine fails to evoke ␤AR up-regulation or supersensitivity (Slotkin et al, 1996;Garofolo et al, 2002), actually impairs the development of the heart rate response to ␤AR stimulation (Hou et al, 1989), and renders receptor stimulation permanently incapable of transducing stimulatory input into growth signals (Hou et al, 1989). Accordingly, after neonatal denervation, ␤AR agonists administered in adulthood cannot elicit the cardiac hypertrophy that normally occurs from receptor stimulation (Hou et al, 1989).…”

Section: Neural Input and The Programming Of Future Cellular Responsimentioning

confidence: 99%

“…The same types of defects can be elicited by central nervous system lesions that reduce peripheral sympathetic neuronal activity without physically disrupting cardiac sympathetic innervation. Again, because the deficiencies involve signaling intermediates that are shared by multiple types of receptors, the interference with the proper programming of cell responses compromises the effects of other neurotransmitters and hormones at the level of cell signaling and a host of physiological responses besides hypertrophy (Hou et al, 1989;Gray et al, 1991;Slotkin et al, 1996). Accordingly, the arrival of ␤AR signals at the developmentally appropriate time helps to program the set-point of reactivity of the end organ so that, if innervation is absent during that period, the target cells do not learn how to produce supersensitivity and become incapable of transducing receptor signals into cellular responses.…”

Section: Neural Input and The Programming Of Future Cellular Responsimentioning

confidence: 99%

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

Slotkin

Auman²,

Seidler

2003

The Journal of Pharmacology and Experimental Therapeutics

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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....

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Section: Ontogenesis Of ␤-Adrenoceptormentioning

confidence: 99%

Section: Neural Input and The Programming Of Future Cellular Responsimentioning

confidence: 99%

Section: Neural Input and The Programming Of Future Cellular Responsimentioning

confidence: 99%

Section: Neural Input and The Programming Of Future Cellular Responsimentioning

confidence: 99%

See 2 more Smart Citations

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

Slotkin

Auman²,

Seidler

2003

The Journal of Pharmacology and Experimental Therapeutics

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“…In the adult, β-adrenergic receptor blockade or the destruction of neuronal inputs to β-adrenergic receptors results in compensatory suprasensitivity of receptor signaling and eventually to upregulation of cell-surface receptors [8]. When these events are triggered in the developing organism, however, there is little or no increase in sensitivity or receptor numbers [9,10]. Therefore, compared with augmented sympathetic activity in adults, increased sympathetic activity in postnatal organisms can produce markedly different qualitative and quantitative response.…”

Section: Introductionmentioning

confidence: 99%

Cardiac hypertrophy in neonatal nephrectomized rats: the role of the sympathetic nervous system

et al. 2009

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Cardiac hypertrophy is frequently encountered in patients with renal failure and represents an independent risk factor for cardiovascular morbidity and mortality. The pathogenesis of cardiac hypertrophy is related to multiple factors, including excess adrenergic activity. This study investigated how renal injury in the early stages of life affects the adrenergic system and thereby potentially influences cardiac growth. Biomarkers of cardiac hypertrophy were used to assess adrenergic function. Newborn male Sprague-Dawley rats were allocated to three groups of five rats each: 5/6 nephrectomy (Nx), pair-fed controls (PF), and sham-operated (SH). Nx animals had significantly higher plasma urea nitrogen, serum creatinine, and mean arterial blood pressure. The heart-weight/body-weight ratio of the Nx cohort was higher than SH and PF (p < 0.001) groups. Plasma norepinephrine (NE) of Nx animals was almost twofold higher than SH and PF (p < 0.01) animals. Compared with SH and PF, Nx animals had higher alpha1A-receptor protein expression, lower cardiac beta1- and beta2-receptor protein expression (p < 0.05), but higher G-protein-coupled receptor kinase-2 (GRK2) expression (p < 0.05). Norepinephrine transporter protein (NET) and renalase protein expression in cardiac tissue from Nx pups were significantly lower than SH and PF. Our data suggest that early age Nx animals have increased circulating catecholamines due to decreased NE metabolism. Enhancement of cardiac GRK2 and NE can contribute to cardiac hypertrophy seen in Nx animals. Furthermore, AKT (activated via alpha1A receptors), as well as increased alpha1A receptors and their agonist NE, might contribute to the observed hypertrophy.

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Prenatal β2-Adrenergic Receptor Signaling and Autism:

Connors

2008

Autism

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Ontogeny of β-adrenoceptor/adenylyl cyclase desensitization mechanisms: the role of neonatal innervation

Cited by 16 publications

References 31 publications

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

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

Cardiac hypertrophy in neonatal nephrectomized rats: the role of the sympathetic nervous system

Prenatal β2-Adrenergic Receptor Signaling and Autism:

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