Receptor-specific mechanisms of desensitization of β-adrenergic receptor function

Hertel, Cornelia; Perkins, John P.

doi:10.1016/0303-7207(84)90094-7

Cited by 73 publications

(31 citation statements)

References 40 publications

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“…These prior studies have demonstrated two primary mechanisms of desensitization, which have been referred to as homologous and heterologous (3,(14)(15)(16) Gs LABELING Figure 7. G, reconstitution data are summarized on the left and G, labeling with cholera toxin ADP-ribosylation is summarized on the right for the animals with saline pumps (open bars) and animals with NE pumps (solid bars).…”

Section: Discussionmentioning

confidence: 99%

Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.

Vatner

Nejima

et al. 1989

J. Clin. Invest.

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The goal of this study was to determine the mechanism of ,/-adrenergic receptor desensitization after chronic elevation of circulating NE levels. Osmotic minipumps containing either NE or saline were implanted subcutaneously in dogs for 34 wk. Physiologic desensitization to isoproterenol was confirmed in conscious dogs, i.e., left ventricular dP/dt increased in response to isoproterenol (0.4 ug/kg per min) by 5,625±731 mmHg/s in control dogs with saline pumps, and significantly less, P < 0.01, by 2,093±263 mmHg/s in dogs with NE pumps. Myocardial 13-adrenergic receptor density as determined with 1251-cyanopindolol binding was 49% higher (P < 0.05) in the NE pump group. However, 13-adrenergic receptor agonist binding with isoproterenol demonstrated a significant shift into the low affinity state for the animals with NE pumps. Basal, GTP plus isoproterenol, 5'-guanylylimidodiphosphate, sodium fluoride, and forskolin-stimulated adenylate cyclase activity in the NE pump group were significantly depressed (P < 0.05) by amounts ranging from 20 to 40%. The functional activity of the guanine nucleotide binding protein G. was also reduced (P < 0.05) in animals with NE pumps. Thus, the process of desensitization in response to chronic elevation of NE levels in intact, normal dogs does not involve a decrease in fi-adrenergic receptor density. Rather, it is characterized by reduced adenylate cyclase activation and uncoupling of the 63-adrenergic receptor in association with decreased activity of the GTP-coupling protein G,.

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Section: Discussionmentioning

confidence: 99%

Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.

Vatner

Nejima

et al. 1989

J. Clin. Invest.

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“…Desensitization of 0-adrenergic receptor-coupled adenylate cyclase is generally divided into two major categories (6)(7)(8). One form is referred to as agonist specific or homologous and is distinguished by the fact that only stimulation by 0-adrenergic agonists is attenuated.…”

Section: /?-Adrenergic Receptor-coupled Adenylate Cyclasementioning

confidence: 99%

“…Conversely, agonist-nonspecific or heterologous desensitization is characterized by diminished responsiveness to additional receptor agonists and to nonreceptor activators such as guanine nucleotides and fluoride ion. Investigations of homologous desensitization have demonstrated sequestration or down-regulation of the receptors away from the cell surface in addition to an uncoupling of receptor-adenylate cyclase interaction (6)(7)(8). Homologous desensitization does not appear to be mediated by cAMP as this form of refractoriness can be demonstrated in the absence of cAMP generation (6)(7)(8).…”

Section: /?-Adrenergic Receptor-coupled Adenylate Cyclasementioning

confidence: 99%

“…Investigations of homologous desensitization have demonstrated sequestration or down-regulation of the receptors away from the cell surface in addition to an uncoupling of receptor-adenylate cyclase interaction (6)(7)(8). Homologous desensitization does not appear to be mediated by cAMP as this form of refractoriness can be demonstrated in the absence of cAMP generation (6)(7)(8). Heterologous desensitization, by contrast, does not involve receptor sequestration or down-regulation but instead is primarily associated with functional uncoupling of the receptors from adenylate cyclase.…”

Section: /?-Adrenergic Receptor-coupled Adenylate Cyclasementioning

confidence: 99%

“…Heterologous desensitization, by contrast, does not involve receptor sequestration or down-regulation but instead is primarily associated with functional uncoupling of the receptors from adenylate cyclase. Moreover, heterologous desensitization appears to be mediated, at least partially, by cAMP (6)(7)(8). Since heterologous desensitization is associated with decrements in fluoride ion and guanine nucleotide-stimulated activities (effectors which bypass the receptors) this form of desensitization must, at a minimum, involve alterations in either the regulatory proteins and/or the catalytic moiety of adenylate cyclase.…”

Section: /?-Adrenergic Receptor-coupled Adenylate Cyclasementioning

confidence: 99%

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Phosphorylation of Cell Surface Receptors: A Mechanism for Regulating Signal Transduction Pathways

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Regulation of G Protein–Coupled Receptors

Penn¹,

Benovic²

1998

Comprehensive Physiology

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The sections in this article are: Signaling Via G Protein–Coupled Receptor Pathways G Protein–Coupled Receptors G Proteins Effectors Mechanisms of G Protein–Coupled Receptor Regulation Classification of Desensitization The Beta‐Adrenergic Receptor and Rhodopsin Signaling Pathways: Model Systems of GPR Signaling and Regulation Receptor Phosphorylation And Uncoupling: Rapid Desensitization Receptor Sequestration Receptor Down‐Regulation Receptor Polymorphisms Sensitization Desensitization of Other GPR Pathways Summary

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Receptor-specific mechanisms of desensitization of β-adrenergic receptor function

Cited by 73 publications

References 40 publications

Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.

Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.

Phosphorylation of Cell Surface Receptors: A Mechanism for Regulating Signal Transduction Pathways

Regulation of G Protein–Coupled Receptors

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