Angiotensin type 1A receptor regulates β-arrestin binding of the β2-adrenergic receptor via heterodimerization

Tóth, András; Gyombolai, Pál; Szalai, Bence; Várnai, Péter; Turu, Gábor; Hunyady, László

doi:10.1016/j.mce.2016.11.027

Cited by 24 publications

(25 citation statements)

References 57 publications

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“…one antagonist could block the G protein activation of both receptors [79]. The AT 1 R-β 2 AR heterodimer also influences the β-arrestin binding properties [88]. Dual agonist occupancy potentiates the β 2 AR-β-arrestin recruitment without affecting the β-arrestin binding of AT 1 R. β-arrestin biased AT 1 R agonists, in contrast to the conventional AT 1 R antagonists, could also evoke this phenomenon [88].…”

Section: Dimer Formation Of At 1 R With Other Gpcrsmentioning

confidence: 99%

“…The AT 1 R-β 2 AR heterodimer also influences the β-arrestin binding properties [88]. Dual agonist occupancy potentiates the β 2 AR-β-arrestin recruitment without affecting the β-arrestin binding of AT 1 R. β-arrestin biased AT 1 R agonists, in contrast to the conventional AT 1 R antagonists, could also evoke this phenomenon [88]. These results suggest that some pharmacological effects of β-arrestin-biased AT 1 R agonists may be transmitted by the regulation of β 2 AR leading to unexpected side effects of these drugs.…”

Section: Dimer Formation Of At 1 R With Other Gpcrsmentioning

confidence: 99%

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Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

Tóth

Turu

Hunyady

et al. 2018

Best Practice & Research Clinical Endocrinology & Metab

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AT angiotensin receptor (ATR), a prototypical G protein-coupled receptor (GPCR), is the main receptor, which mediates the effects of the renin-angiotensin system (RAS). ATR plays a crucial role in the regulation of blood pressure and salt-water homeostasis, and in the development of pathological conditions, such as hypertension, heart failure, cardiovascular remodeling, renal fibrosis, inflammation, and metabolic disorders. Stimulation of ATR leads to pleiotropic signal transduction pathways generating arrays of complex cellular responses. Growing amount of evidence shows that ATR is a versatile GPCR, which has multiple unique faces with distinct conformations and signaling properties providing new opportunities for functionally selective pharmacological targeting of the receptor. Biased ligands of ATR have been developed to selectively activate the β-arrestin pathway, which may have therapeutic benefits compared to the conventional angiotensin converting enzyme inhibitors and angiotensin receptor blockers. In this review, we provide a summary about the most recent findings and novel aspects of the ATR function, signaling, regulation, dimerization or oligomerization and its cross-talk with other receptors, including epidermal growth factor (EGF) receptor, adrenergic receptors and CB cannabinoid receptor. Better understanding of the mechanisms and structural aspects of ATR activation and cross-talk can lead to the development of novel type of drugs for the treatment of cardiovascular and other diseases.

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Section: Dimer Formation Of At 1 R With Other Gpcrsmentioning

confidence: 99%

Section: Dimer Formation Of At 1 R With Other Gpcrsmentioning

confidence: 99%

Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

Tóth

Turu

Hunyady

et al. 2018

Best Practice & Research Clinical Endocrinology & Metab

Self Cite

View full text Add to dashboard Cite

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“…Another possibility is the involvement of a yet-to-be unidentified protein in close proximity with the AT 1 R that preferentially recruits GRK2 (over GRK5) in AZG cell membranes. Interestingly, the AT 1 R was recently shown to heterodimerize with the β 2 AR, enhancing βarrestin2 interaction with the latter receptor in transfected HEK293 cells [29]. Although no GRK involvement in this was examined, this study raises the intriguing possibility that AT 1 Rs and βARs form heterodimers also in AZG cells and that these heterodimers then become substrates for GRK2 only, enhancing βarrestin1 recruitment and downstream signaling to aldosterone production.…”

Section: Discussionmentioning

confidence: 80%

GRK2-Mediated Crosstalk Between β-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo

Pollard

Ghandour

Cora

et al. 2020

IJMS

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Aldosterone is produced by adrenocortical zona glomerulosa (AZG) cells in response to angiotensin II (AngII) acting through its type I receptors (AT1Rs). AT1R is a G protein-coupled receptor (GPCR) that induces aldosterone via both G proteins and the adapter protein βarrestin1, which binds the receptor following its phosphorylation by GPCR-kinases (GRKs) to initiate G protein-independent signaling. β-adrenergic receptors (ARs) also induce aldosterone production in AZG cells. Herein, we investigated whether GRK2 or GRK5, the two major adrenal GRKs, is involved in the catecholaminergic regulation of AngII-dependent aldosterone production. In human AZG (H295R) cells in vitro, the βAR agonist isoproterenol significantly augmented both AngII-dependent aldosterone secretion and synthesis, as measured by the steroidogenic acute regulatory (StAR) protein and CYP11B2 (aldosterone synthase) mRNA inductions. Importantly, GRK2, but not GRK5, was indispensable for the βAR-mediated enhancement of aldosterone in response to AngII. Specifically, GRK2 inhibition with Cmpd101 abolished isoproterenol’s effects on AngII-induced aldosterone synthesis/secretion, whereas the GRK5 knockout via CRISPR/Cas9 had no effect. It is worth noting that these findings were confirmed in vivo, since rats overexpressing GRK2, but not GRK5, in their adrenals had elevated circulating aldosterone levels compared to the control animals. However, treatment with the β-blocker propranolol prevented hyperaldosteronism in the adrenal GRK2-overexpressing rats. In conclusion, GRK2 mediates a βAR-AT1R signaling crosstalk in the adrenal cortex leading to elevated aldosterone production. This suggests that adrenal GRK2 may be a molecular link connecting the sympathetic nervous and renin-angiotensin systems at the level of the adrenal cortex and that its inhibition might be therapeutically advantageous in hyperaldosteronism-related conditions.

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“…β-arrestin, which is known as one of the adaptor proteins, interacts with β 2 -AR 19) and the interaction of β 2 -AR and AT 1 R is suggested to promote the interaction of β-arrestin with β 2 -AR. 20,21) Because β-arrestin 2 is likely to regulate γ-secretase activity, 22) the binding of Telm on AT 1 R causes the conformational change of AT 1 R that could promote the interaction of β-arrestin with β 2 -AR, resulting in an increase in γ-secretase activity.…”

Section: Discussionmentioning

confidence: 99%

Interaction between Angiotensin Receptor and β-Adrenergic Receptor Regulates the Production of Amyloid β-Protein

Kikuchi

Fujita

Shen

et al. 2020

Biological & Pharmaceutical Bulletin

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Alzheimer's disease (AD) is characterized by the formation of extracellular amyloid plaques containing the amyloid β-protein (Aβ) within the parenchyma of the brain. Aβ is considered to be the key pathogenic factor of AD. Recently, we showed that Angiotensin II type 1 receptor (AT 1 R), which regulates blood pressure, is involved in Aβ production, and that telmisartan (Telm), which is an angiotensin II receptor blocker (ARB), increased Aβ production via AT 1 R. However, the precise mechanism underlying how AT 1 R is involved in Aβ production is unknown. Interestingly, AT 1 R, a G protein-coupled receptor, was strongly suggested to be involved in signal transduction by heterodimerization with β 2-adrenergic receptor (β 2-AR), which is also shown to be involved in Aβ generation. Therefore, in this study, we aimed to clarify whether the interaction between AT 1 R and β 2-AR is involved in the regulation of Aβ production. To address this, we analyzed whether the increase in Aβ production by Telm treatment is affected by β-AR antagonist using fibroblasts overexpressing amyloid precursor protein (APP). We found that the increase in Aβ production by Telm treatment was decreased by the treatment of β 2-AR selective antagonist ICI-118551 more strongly than the treatment of β 1-AR selective antagonists. Furthermore, deficiency of AT 1 R abolished the effect of β 2-AR antagonist on the stimulation of Aβ production caused by Telm. Taken together, the interaction between AT 1 R and β 2-AR is likely to be involved in Aβ production.

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Angiotensin type 1A receptor regulates β-arrestin binding of the β2-adrenergic receptor via heterodimerization

Cited by 24 publications

References 57 publications

Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

GRK2-Mediated Crosstalk Between β-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo

Interaction between Angiotensin Receptor and β-Adrenergic Receptor Regulates the Production of Amyloid β-Protein

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