The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato, Priscila Y.; Chuprun, J. Kurt; Schwartz, Mathew; Koch, Walter J.

doi:10.1152/physrev.00015.2014

Cited by 125 publications

(159 citation statements)

References 285 publications

(342 reference statements)

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“…GRK2 activity has increasingly been shown to contribute to the progression of numerous diseases and organ dysfunction 5, 6 . For instance, a large body of work over the last two decades has identified GRK2 as a major regulator of cardiac dysfunction, wherein genetic ablation or inhibition of GRK2 is sufficient to protect the heart from ischemic insult, prevent adverse cardiac remodeling during chronic HF and prevent βAR desensitization to enhance cardiomyocyte contractility 4, 14–17 .…”

Section: Discussionmentioning

confidence: 99%

“…βAR desensitization has long been recognized as a contributing factor to the progression of various disease states and is largely mediated via regulation by G protein-coupled receptor kinase (GRK)-dependent processes 4, 5 . Upon βAR stimulation, GRK-dependent phosphorylation of the C-terminus of the receptor increases the recruitment of βarrestins (βarr), multifunctional scaffolding proteins that sterically interdict the association between βAR and active G proteins, as well as engage receptor internalization, mechanisms that act to arrest G protein-dependent βAR signaling and desensitize the receptor to prolonged stimulation.…”

Section: Introductionmentioning

confidence: 99%

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Impact of paroxetine on proximal β-adrenergic receptor signaling

Guo

Carter

Grisanti

et al. 2017

Cellular Signalling

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β-adrenergic receptors (βAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of βAR has long been recognized as a maladaptive process in the progression of various disease states. Thus, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts. Via structural and biochemical analyses, the selective serotonin reuptake inhibitor (SSRI) paroxetine was identified as a GRK2 inhibitor that enhances βAR-dependent cardiomyocyte and cardiac contractility and reverses cardiac dysfunction and myocardial βAR expression in mouse models of heart failure. Despite these functional outcomes, consistent with diminished βAR desensitization, the proximal βAR signaling mechanisms sensitive to paroxetine have not been reported. In this study, we aimed to determine whether paroxetine prevents classic βAR desensitization-related signaling mechanisms at a molecular level. Therefore, via immunoblotting, radioligand binding, fluorescence resonance energy transfer (FRET) and microscopy assays, we have performed an assessment of the effect of paroxetine on proximal βAR signaling responses. Indeed, paroxetine treatment inhibited ligand-induced β2AR phosphorylation in a concentration-dependent manner. Additionally, for both β1AR and β2AR, paroxetine decreased ligand-induced βarrestin2 recruitment and subsequent receptor internalization. Thus, paroxetine inhibits βAR desensitization mechanisms consistent with GRK2 inhibition and provides a useful pharmacological tool for studying these proximal GPCR signaling responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of paroxetine on proximal β-adrenergic receptor signaling

Guo

Carter

Grisanti

et al. 2017

Cellular Signalling

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“…A decreased β-AR function has been reported in heart failure, which may also be associated with SAN dysfunction (28). In this case, SAN failure occurs via a decreased β-AR expression, together with an increase in GRK activity in the heart and mirrored in some cases, in peripheral blood mononuclear cells (28)(29)(30)(31), both in humans (28,29,(32)(33)(34)(35) and in experimental models (34)(35)(36)(37)(38). A decreased expression and an increased desensitization of β-AR directly led to a loss of β-adrenergic function in the failing heart (28).…”

Section: R420qmentioning

confidence: 96%

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

Wang¹,

Mesirca²,

Marqués-Sulé³

et al. 2017

JCI Insight

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“…Equally important to the stimulation and activation of GPCRs is the desensitization and "shutting-off" of the receptor. This task is primarily conducted by the GPCR kinase (GRK) family of proteins (2,3). GRK2 is ubiquitously expressed throughout the tissues of the body, perhaps most notably in the heart where its regulation of adrenergic receptors (ARs) is critical to physiological heart function.…”

mentioning

confidence: 99%

“…Many of the prominent effects of GRK2 in the heart are mediated by regulation of the ␤ 2 AR (2,14). This receptor is also expressed in skeletal muscle and modulates various aspects of skeletal muscle physiology.…”

mentioning

confidence: 99%

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy

Woodall

Luongo

et al. 2016

Journal of Biological Chemistry

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GRK2, a G protein-coupled receptor kinase, plays a critical role in cardiac physiology. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 activity in the heart directly correlate with cardiac contractile function. Furthermore, increased expression of GRK2 after cardiac insult exacerbates injury and speeds progression to heart failure. Despite the importance of this kinase in both the physiology and pathophysiology of the heart, relatively little is known about the role of GRK2 in skeletal muscle function and disease. In this study we generated a novel skeletal muscle-specific GRK2 knock-out (KO) mouse (MLC-Cre:GRK2 fl/fl ) to gain a better understanding of the role of GRK2 in skeletal muscle physiology. In isolated muscle mechanics testing, GRK2 ablation caused a significant decrease in the specific force of contraction of the fast-twitch extensor digitorum longus muscle yet had no effect on the slow-twitch soleus muscle. Despite these effects in isolated muscle, exercise capacity was not altered in MLC-Cre:GRK2 fl/fl mice compared with wild-type controls. Skeletal muscle hypertrophy stimulated by clenbuterol, a ␤ 2 -adrenergic receptor (␤ 2 AR) agonist, was significantly enhanced in MLC-Cre:GRK2 fl/fl mice; mechanistically, this seems to be due to increased clenbuterol-stimulated pro-hypertrophic Akt signaling in the GRK2 KO skeletal muscle. In summary, our study provides the first insights into the role of GRK2 in skeletal muscle physiology and points to a role for GRK2 as a modulator of contractile properties in skeletal muscle as well as ␤ 2 AR-induced hypertrophy. G protein-coupled receptors (GPCRs)2 comprise the largest family of membrane proteins in the genome. GPCRs regulate diverse processes throughout the body by responding to a vast array of extracellular stimuli including hormones, neurotransmitters, and photons of light (1). Equally important to the stimulation and activation of GPCRs is the desensitization and "shutting-off" of the receptor. This task is primarily conducted by the GPCR kinase (GRK) family of proteins (2, 3). GRK2 is ubiquitously expressed throughout the tissues of the body, perhaps most notably in the heart where its regulation of adrenergic receptors (ARs) is critical to physiological heart function. Cardiac overexpression of GRK2 in mice suppresses contractility, whereas cardiac overexpression of the GRK2 inhibitor ␤ARKct (a C-terminal peptide that competes with GRK2 binding to G ␤␥ ) enhances contractile function (4). Catecholamine overdrive during heart failure drives increased GRK2 expression in the cardiomyocyte, ultimately leading to excessive desensitization of ␤ARs, loss of receptor density, and a drop in inotropic reserve (5-7). Indeed, myocardial inhibition or deletion of GRK2 can prevent and even reverse heart failure in numerous animal models (4, 8 -13).Although we have a firm understanding of the role of GRK2 in the physiology and pathophysiology of t...

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The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Cited by 125 publications

References 285 publications

Impact of paroxetine on proximal β-adrenergic receptor signaling

Impact of paroxetine on proximal β-adrenergic receptor signaling

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy

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