Paroxetine-Mediated GRK2 Inhibition Reverses Cardiac Dysfunction and Remodeling After Myocardial Infarction

Schumacher, Sarah M.; Gao, Erhe; Zhu, Wuqiang; Chen, Xiongwen; Chuprun, J. Kurt; Feldman, Arthur M.; Tesmer, John J.G.; Koch, Walter J.

doi:10.1016/j.cardfail.2015.06.318

Cited by 35 publications

(57 citation statements)

References 36 publications

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“…In summary, we have utilised a variety of small molecule GRK2 inhibitors to confirm for the first time the central role that GRK2 plays in the regulation of vasoconstrictor mediated arterial tone, which highlights a potentially novel strategy for blood pressure regulation through targeting GRK2 function. The results also suggest that some of the benefit of applying small molecule inhibitors of GRK2 systemically (Schumacher et al, 2015) is to improve the hormonal responsiveness of smooth muscle cells in addition to that of cardiac myocytes.…”

mentioning

confidence: 76%

“…Therefore, identification of small molecule GRK inhibitors is vital to confirm the role that GRKs play in whole body physiology and develop potential new therapeutic strategies. Because the SSRI paroxetine has been reported to inhibit GRK2 activity not only against in vitro substrates such as tubulin and isolated rhodopsin, but also in whole cell systems (Schumacher et al, 2015;Thal et al, 2011), we investigated whether paroxetine could prevent desensitization of GRK2 mediated GPCR activity in arterial rings.…”

Section: Discussionmentioning

confidence: 99%

“…However, the report that the selective serotonin reuptake inhibitor (SSRI) paroxetine can inhibit GRK2 function (Thal et al, 2011), prompted us to examine whether this drug can provide a pharmacological means to delineate a role for GRK2 in vasoconstrictor-mediated vessel desensitization. Furthermore, paroxetine has also been shown to enhance -adrenoceptormediated contraction of cardiomyocytes (Thal et al, 2012), a process regulated by GRK2 (Koch et al, 1995;Williams et al, 2004), and to improve cardiac function post-myocardial infarction (Schumacher et al, 2015).…”

Section: Mol #112524mentioning

confidence: 99%

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Small-Molecule G Protein–Coupled Receptor Kinase Inhibitors Attenuate G Protein–Coupled Receptor Kinase 2–Mediated Desensitization of Vasoconstrictor-Induced Arterial Contractions

et al. 2018

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confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Mol #112524mentioning

confidence: 99%

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Small-Molecule G Protein–Coupled Receptor Kinase Inhibitors Attenuate G Protein–Coupled Receptor Kinase 2–Mediated Desensitization of Vasoconstrictor-Induced Arterial Contractions

et al. 2018

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“…Pumps were filled following the manufacturer's specifications with sterile PBS or clenbuterol (3 mg/kg per day) and inserted as previously described (35). Briefly, mice were anesthetized with isoflurane (2.5% v/v), and pumps were implanted subcutaneously through a subscapular incision, which was then closed using 4.0 silk suture (Ethicon).…”

Section: Methodsmentioning

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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“…While GRK2 overexpression caused attenuation of βAR-induced contractility and reduced adenylyl cyclase coupling, GRK2-CT overexpression led to enhanced cardiac contractility (49). GRK2-CT has been further shown to act as an inhibitor of endogenous GRK2 in a variety of experimental systems ranging from cells to mice (50,51). We therefore used a GRK2-CT gene expression approach to determine if inhibiting GRK2 could rescue the defective cardiac function that arises from Mdm2 deletion.…”

Section: Expression Levels Of β-Arrestins and Grk2 In Mdm2/p53-ko Heamentioning

confidence: 99%

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

Jean-Charles¹,

Yu²,

Abraham³

et al. 2017

JCI Insight

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Paroxetine-Mediated GRK2 Inhibition Reverses Cardiac Dysfunction and Remodeling After Myocardial Infarction

Cited by 35 publications

References 36 publications

Small-Molecule G Protein–Coupled Receptor Kinase Inhibitors Attenuate G Protein–Coupled Receptor Kinase 2–Mediated Desensitization of Vasoconstrictor-Induced Arterial Contractions

Small-Molecule G Protein–Coupled Receptor Kinase Inhibitors Attenuate G Protein–Coupled Receptor Kinase 2–Mediated Desensitization of Vasoconstrictor-Induced Arterial Contractions

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

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

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