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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Tachyphylaxis is described as a rapid decrease in response to a drug after repeated or continuous administration of the same drug dose. It is a phenomenon where the body becomes less responsive to a particular substance or intervention over time, requiring higher doses or stronger interventions to achieve the same effect. It results from adaptive changes in the body's receptors, signaling pathways, or physiological processes that occur in response to prolonged exposure to a stimulus.
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Postganglionic sympathetic fibers (except those supplying the sweat glands) releasing noradrenaline or norepinephrine are called noradrenergic or adrenergic neurons. Noradrenaline, dopamine, adrenaline, or epinephrine are collectively called "catecholamines" as they contain a catechol moiety and an amine side chain. The five stages of neurotransmitter release involve their synthesis, storage, release, reuptake and metabolism.
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Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications
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Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.

D E Vatner1, S F Vatner, J Nejima

  • 1Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston 02114.

The Journal of Clinical Investigation
|December 1, 1989
PubMed
Summary

Chronic elevation of norepinephrine (NE) leads to beta-adrenergic receptor desensitization, not by reducing receptor density, but by decreasing adenylate cyclase activity and Gs protein function.

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Area of Science:

  • Cardiovascular Physiology
  • Molecular Pharmacology
  • Adrenergic Signaling

Background:

  • Chronic elevation of circulating norepinephrine (NE) can lead to beta-adrenergic receptor desensitization.
  • Understanding the precise mechanism of this desensitization is crucial for cardiovascular health.

Purpose of the Study:

  • To elucidate the mechanism underlying beta-adrenergic receptor desensitization following chronic elevation of NE levels.
  • To investigate the role of receptor density, affinity, and downstream signaling pathways.

Main Methods:

  • Chronic NE infusion via osmotic minipumps in dogs for 3-4 weeks.
  • Assessment of physiological response to isoproterenol (cardiac contractility).
  • Measurement of myocardial beta-adrenergic receptor density and affinity.
  • Analysis of adenylate cyclase activity and guanine nucleotide-binding protein Gs function.

Main Results:

  • Physiological desensitization to isoproterenol was confirmed.
  • Beta-adrenergic receptor density was not decreased; rather, agonist binding affinity shifted to a low-affinity state.
  • Adenylate cyclase activity was significantly depressed (20-40%).
  • Functional activity of the Gs protein was also reduced.

Conclusions:

  • Beta-adrenergic receptor desensitization from chronic NE elevation in dogs does not involve reduced receptor density.
  • The process is characterized by receptor uncoupling and impaired adenylate cyclase activation.
  • Decreased activity of the GTP-binding protein Gs contributes to this desensitization.