Molecular mechanisms of G protein-coupled receptor desensitization and resensitization

Initially thought to play a role only in G-protein-coupled receptor desensitization, β-arrestins are ascribed with new roles such as scaffolding and signaling proteins by their own right. This review explores the many functions of β-arrestins, with an emphasis on their recently identified role as regulators of receptor signaling.

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Pleiotropic Role for GRKs and b-Arrestins in Receptor Regulation

Physiology ◽

10.1152/physiologyonline.1997.12.4.145 ◽

1997 ◽

Vol 12 (4) ◽

pp. 145-152 ◽

Cited By ~ 1

Author(s):

SSG Ferguson ◽

J Zhang ◽

LS Barak ◽

MG Caron

Keyword(s):

Angiotensin Ii ◽

G Protein ◽

Intracellular Trafficking ◽

Coated Vesicle ◽

Receptor Regulation ◽

Receptor Desensitization ◽

G Protein Coupled Receptor ◽

Receptor Kinases ◽

Trafficking Molecules ◽

G Protein Coupled

G protein-coupled receptor kinases and arrestin proteins are well-characterized mediators of agonist-dependent G protein-coupled receptor desensitization. These proteins are now shown to play a dual role in receptor regulation by mediating both receptor uncoupling and sequestration, a process important for receptor resensitization. b-Arrestins bound to phosporylated b2-adrenergic and angiotensin II type 1A receptors act as intracellular trafficking molecules specifically targeting these receptors for dynamin-dependent clathrin-coated vesicle-mediated sequestration.

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Molecular mechanisms of G protein-coupled receptor signaling in the modulation of anxiety and conditioned fear

IBRO Reports ◽

10.1016/j.ibror.2019.07.1517 ◽

2019 ◽

Vol 6 ◽

pp. S483

Author(s):

Meejung Ko ◽

Terrance Chiang ◽

Arbaaz Mukadam ◽

Grace Mulia ◽

Julia Chester ◽

...

Keyword(s):

G Protein ◽

Molecular Mechanisms ◽

Conditioned Fear ◽

Receptor Signaling ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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Role of Endothelial G Protein-Coupled Receptor Kinase 2 in Angioedema

Hypertension ◽

10.1161/hypertensionaha.120.15130 ◽

2020 ◽

Vol 76 (5) ◽

pp. 1625-1636 ◽

Cited By ~ 1

Author(s):

Jessica Gambardella ◽

Daniela Sorriento ◽

Maria Bova ◽

Mariarosaria Rusciano ◽

Stefania Loffredo ◽

...

Keyword(s):

Vascular Permeability ◽

G Protein ◽

Molecular Mechanisms ◽

No Production ◽

Receptor Kinase ◽

Severe Phenotype ◽

G Protein Coupled Receptor ◽

G Protein Coupled

Excessive BK (bradykinin) stimulation is responsible for the exaggerated permeabilization of the endothelium in angioedema. However, the molecular mechanisms underlying these responses have not been investigated. BK receptors are Gq-protein-coupled receptors phosphorylated by GRK2 (G protein-coupled receptor kinase 2) with a hitherto unknown biological and pathophysiological significance. In the present study, we sought to identify the functional role of GRK2 in angioedema through the regulation of BK signaling. We found that the accumulation of cytosolic Ca 2+ in endothelial cells induced by BK was sensitive to GRK2 activity, as it was significantly augmented by inhibiting the kinase. Accordingly, permeabilization and NO production induced by BK were enhanced, as well. In vivo, mice with reduced GRK2 levels in the endothelium (Tie2-CRE/GRK2 fl+/fl − ) exhibited an increased response to BK in terms of vascular permeability and extravasation. Finally, patients with reduced GRK2 levels displayed a severe phenotype of angioedema. Taken together, these findings establish GRK2 as a novel pivotal regulator of BK signaling with an essential role in the pathophysiology of vascular permeability and angioedema.

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