GRKs as Modulators of Neurotransmitter Receptors

Gurevich, Eugenia V.; Gurevich, Vsevolod V.

doi:10.3390/cells10010052

Cited by 19 publications

(22 citation statements)

References 170 publications

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“…Surprisingly, we observe an increase in ICL2 phosphorylation at S105 and S110 in the GRK2 KO cells and S110 in the GRK6 KO cells, suggesting potential compensatory phosphorylation at S105 and S110 by other kinases in these cell lines and hierarchical phosphorylation of APH1A by GRKs. Indeed, GRKs are known to act hierarchically to mediate ICL and C-terminal phosphorylation of many GPCRs to regulate downstream functional signaling outcomes (Gurevich and Gurevich, 2020;Kim et al, 2004;Kouhen et al, 2000;Palmer and Stiles, 2000). We also detect an increase in Ab generation following chemical inhibition of GRK2/3 in human fAD NPCs (Figure 2C).…”

Section: Discussionmentioning

confidence: 69%

GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation

Todd¹,

Huang²,

Lee³

et al. 2022

Cell Reports

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Section: Discussionmentioning

confidence: 69%

GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation

Todd¹,

Huang²,

Lee³

et al. 2022

Cell Reports

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“…Since the major role of GRK phosphorylation is to drive or enhance β-arrestin recruitment to GPCRs [ 5 ], we evaluated this functional process within the context of various D1R mutants that had specific alterations in their phosphorylation sites. Using a combination of truncations, forward (loss of phosphorylation) and reverse (gain of phosphorylation) mutations, along with two different β-arrestin recruitment assays, we determined that GRK-mediated phosphorylation of both residues comprising the T5/S6 cluster (T360 and S362) within the proximal C-terminus serves as a major driver for β-arrestin recruitment to the D1R.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to G protein-mediated signaling, all activated GPCRs recruit scaffolding proteins from the arrestin family that consists of four members—arrestins 1 and 4 that are restricted to the visual system, and arrestins 2 and 3, more commonly referred to as β-arrestin 1 and 2, respectively, which are ubiquitously found in most cell types [ 4 ]. Recruitment of β-arrestin initiates receptor desensitization and internalization [ 5 ], but is also recognized to independently activate distinct downstream signaling cascades [ 4 , 6 ]. The desensitization process initiated by β-arrestin recruitment is typically linked to phosphorylation of GPCRs by serine/threonine protein kinases [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Delineation of G Protein-Coupled Receptor Kinase Phosphorylation Sites within the D1 Dopamine Receptor and Their Roles in Modulating β-Arrestin Binding and Activation

Moritz

Madaras

Rankin

et al. 2023

IJMS

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The D1 dopamine receptor (D1R) is a G protein-coupled receptor that signals through activating adenylyl cyclase and raising intracellular cAMP levels. When activated, the D1R also recruits the scaffolding protein β-arrestin, which promotes receptor desensitization and internalization, as well as additional downstream signaling pathways. These processes are triggered through receptor phosphorylation by G protein-coupled receptor kinases (GRKs), although the precise phosphorylation sites and their role in recruiting β-arrestin to the D1R remains incompletely described. In this study, we have used detailed mutational and in situ phosphorylation analyses to completely identify the GRK-mediated phosphorylation sites on the D1R. Our results indicate that GRKs can phosphorylate 14 serine and threonine residues within the C-terminus and the third intracellular loop (ICL3) of the receptor, and that this occurs in a hierarchical fashion, where phosphorylation of the C-terminus precedes that of the ICL3. Using β-arrestin recruitment assays, we identified a cluster of phosphorylation sites in the proximal region of the C-terminus that drive β-arrestin binding to the D1R. We further provide evidence that phosphorylation sites in the ICL3 are responsible for β-arrestin activation, leading to receptor internalization. Our results suggest that distinct D1R GRK phosphorylation sites are involved in β-arrestin binding and activation.

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“…11–13 In addition, because the receptor-β-arrestin complex traffics inside the cell to either reach the lysosome for degradation (receptor downregulation) or return to the plasma membrane ready for another round of activation (resensitization), β-arrestins can mediate G protein-independent signaling through effector scaffolding. 11–14 Of note, the 2 main cardiac βAR subtypes have some fundamental differences in their functional and signaling features. For instance, the β 1 AR is by far the predominant subtype expressed at an ∼3:1 ratio compared with the β 2 AR in cardiac myocytes 15,16 and is proapoptotic, whereas the β 2 AR is antiapoptotic.…”

Section: Introductionmentioning

confidence: 99%

Adrenal G Protein-Coupled Receptors and the Failing Heart: A Long-distance, Yet Intimate Affair

Borges

Ferraino

Cora

et al. 2022

Journal of Cardiovascular Pharmacology

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:Systolic heart failure (HF) is a chronic clinical syndrome characterized by the reduction in cardiac function and still remains the disease with the highest mortality worldwide. Despite considerable advances in pharmacological treatment, HF represents a severe clinical and social burden. Chronic human HF is characterized by several important neurohormonal perturbations, emanating from both the autonomic nervous system and the adrenal glands. Circulating catecholamines (norepinephrine and epinephrine) and aldosterone elevations are among the salient alterations that confer significant hormonal burden on the already compromised function of the failing heart. This is why sympatholytic treatments (such as β-blockers) and renin-angiotensin system inhibitors or mineralocorticoid receptor antagonists, which block the effects of angiotensin II (AngII) and aldosterone on the failing heart, are part of the mainstay HF pharmacotherapy presently. The adrenal gland plays an important role in the modulation of cardiac neurohormonal stress because it is the source of almost all aldosterone, of all epinephrine, and of a significant amount of norepinephrine reaching the failing myocardium from the blood circulation. Synthesis and release of these hormones in the adrenals is tightly regulated by adrenal G protein-coupled receptors (GPCRs), such as adrenergic receptors and AngII receptors. In this review, we discuss important aspects of adrenal GPCR signaling and regulation, as they pertain to modulation of cardiac function in the context of chronic HF, by focusing on the 2 best studied adrenal GPCR types in that context, adrenergic receptors and AngII receptors (AT1Rs). Particular emphasis is given to findings from the past decade and a half that highlight the emerging roles of the GPCR-kinases and the β-arrestins in the adrenals, 2 protein families that regulate the signaling and functioning of GPCRs in all tissues, including the myocardium and the adrenal gland.

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GRKs as Modulators of Neurotransmitter Receptors

Cited by 19 publications

References 170 publications

GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation

GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation

Delineation of G Protein-Coupled Receptor Kinase Phosphorylation Sites within the D1 Dopamine Receptor and Their Roles in Modulating β-Arrestin Binding and Activation

Adrenal G Protein-Coupled Receptors and the Failing Heart: A Long-distance, Yet Intimate Affair

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