scholarly journals Hypothesis

2016 ◽  
Vol 22 (1) ◽  
pp. 51-53 ◽  
Author(s):  
Jonathan M. Powell ◽  
Emanuel Ebin ◽  
Steven Borzak ◽  
Anastasios Lymperopoulos ◽  
Charles H. Hennekens
Keyword(s):  
G Protein ◽  
Wall Thickness ◽  
Basic Research ◽  
Left Ventricular ◽  
Conditional Knockout ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

The hypothesis that paroxetine decreases morbidity and mortality in patients with heart failure (HF) is plausible but unproven. Basic research demonstrates that inhibition of G protein-coupled receptor kinase 2 (GRK2) both in vitro and in vivo in the myocardium may be beneficial. G protein-coupled receptor kinase 2 antagonism is purported to exert cardioprotective effects immediately following myocardial injury by blunting toxic overstimulation on a recently injured heart. In addition, chronic overexpression of GRK2 inhibits catecholamine induction of vital positive chronotropic and ionotropic effects required to preserve cardiac output leading to worsening of congestive HF. In cardiac-specific GRK2 conditional knockout mice, there is significant improvement in left ventricular wall thickness, left ventricular end-diastolic diameter (LVEDD), and ejection fraction (EF) compared to controls. Paroxetine is a selective serotonin reuptake inhibitor which was recently shown to have the ability to directly inhibit GRK2 both in vitro and in vivo. At physiologic temperatures, paroxetine inhibits GRK2-dependent phosphorylation of an activated G-protein-coupled receptor with a half maximal inhibitory concentration of 35 micromoles, a substantially greater affinity than for other G protein-coupled receptor kinases. In a randomized trial in mice with systolic HF and depressed EF postmyocardial infarction, those treated with paroxetine had a 30% increase in EF, improved contractility, and LVEDD and wall thickness compared to those treated with medical therapy alone. While further basic research may continue to elucidate plausible mechanisms of benefit and observational studies will contribute important relevant information, large scale randomized trials designed a priori to do so are necessary to test the hypothesis.

scholarly journals β-Arrestin 1 and 2 and G Protein-Coupled Receptor Kinase 2 Expression in Pituitary Adenomas: Role in the Regulation of Response to Somatostatin Analogue Treatment in Patients With Acromegaly

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4715-4725 ◽  
Author(s):  
Federico Gatto ◽  
Richard Feelders ◽  
Rob van der Pas ◽  
Johan M. Kros ◽  
Fadime Dogan ◽  
...  
Keyword(s):  
G Protein ◽  
Pituitary Adenomas ◽  
Somatostatin Analogue ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Sstr Subtype ◽  
G Protein Coupled ◽  
Grk2 Expression

Recent in vitro studies highlighted G protein-coupled receptor kinase (GRK)2 and β-arrestins as important players in driving somatostatin receptor (SSTR) desensitization and trafficking. Our aim was to characterize GRK2 and β-arrestins expression in different pituitary adenomas and to investigate their potential role in the response to somatostatin analog (SSA) treatment in GH-secreting adenomas (GHomas). We evaluated mRNA expression of multiple SSTRs, GRK2, β-arrestin 1, and β-arrestin 2 in 41 pituitary adenomas (31 GHomas, 6 nonfunctioning [NFPAs], and 4 prolactinomas [PRLomas]). Within the GHomas group, mRNA data were correlated with the in vivo response to an acute octreotide test and with the GH-lowering effect of SSA in cultured primary cells. β-Arrestin 1 expression was low in all 3 adenoma histotypes. However, its expression was significantly lower in GHomas and PRLomas, compared with NFPAs (P < .01). GRK2 expression was higher in PRLomas and NFPAs compared with GHomas (P < .05). In the GHoma group, GRK2 expression was inversely correlated to β-arrestin 1 (P < .05) and positively correlated to β-arrestin 2 (P < .0001). SSA treatment did not affect GRK2 and β-arrestin expression in GHomas or in cultured rat pituitary tumor GH3 cells. Noteworthy, β-arrestin 1 was significantly lower (P < .05) in tumors responsive to octreotide treatment in vitro, whereas GRK2 and SSTR subtype 2 were significantly higher (P < .05). Likewise, β-arrestin 1 levels were inversely correlated with the in vivo response to acute octreotide test (P = .001), whereas GRK2 and SSTR subtype 2 expression were positively correlated (P < .05). In conclusion, for the first time, we characterized GRK2, β-arrestin 1, and β-arrestin 2 expression in a representative number of pituitary adenomas. β-Arrestin 1 and GRK2 seem to have a role in modulating GH secretion during SSA treatment.

scholarly journals Vascular Abnormalities in Mice Deficient for the G Protein-Coupled Receptor GPR4 That Functions as a pH Sensor

2006 ◽  
Vol 27 (4) ◽  
pp. 1334-1347 ◽  
Author(s):  
Li V. Yang ◽  
Caius G. Radu ◽  
Meenakshi Roy ◽  
Sunyoung Lee ◽  
Jami McLaughlin ◽  
...  
Keyword(s):  
G Protein ◽  
Mesangial Cells ◽  
Ex Vivo ◽  
Extracellular Ph ◽  
Ph Sensing ◽  
G Protein Coupled Receptor ◽  
Vascular Abnormalities ◽  
G Protein Coupled

ABSTRACT GPR4 is a G protein-coupled receptor expressed in the vasculature, lung, kidney, and other tissues. In vitro ectopic overexpression studies implicated GPR4 in sensing extracellular pH changes leading to cyclic AMP (cAMP) production. To investigate its biological roles in vivo, we generated GPR4-deficient mice by homologous recombination. Whereas GPR4-null adult mice appeared phenotypically normal, neonates showed a higher frequency of perinatal mortality. The average litter size from GPR4−/− intercrosses was ∼30% smaller than that from GPR4+/+ intercrosses on N3 and N5 C57BL/6 genetic backgrounds. A fraction of knockout embryos and neonates had spontaneous hemorrhages, dilated and tortuous subcutaneous blood vessels, and defective vascular smooth muscle cell coverage. Mesangial cells in kidney glomeruli were also significantly reduced in GPR4-null neonates. Some neonates exhibited respiratory distress with airway lining cell metaplasia. To examine whether GPR4 is functionally involved in vascular pH sensing, an ex vivo aortic ring assay was used under defined pH conditions. Compared to wild-type aortas, microvessel outgrowth from GPR4-null aortas was less inhibited by acidic extracellular pH. Treatment with an analog of cAMP, a downstream effector of GPR4, abolished microvessel outgrowth bypassing the GPR4-knockout phenotype. These results suggest that GPR4 deficiency leads to partially penetrant vascular abnormalities during development and that this receptor functions in blood vessel pH sensing.

scholarly journals Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4171-4180 ◽  
Author(s):  
Takashi Nakakura ◽  
Chihiro Mogi ◽  
Masayuki Tobo ◽  
Hideaki Tomura ◽  
Koichi Sato ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Insulin Secretion ◽  
G Protein ◽  
Normal Glucose Tolerance ◽  
Extracellular Ph ◽  
G Protein Coupled Receptor ◽  
Glucose Stimulated Insulin Secretion ◽  
G Protein Coupled

Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown as a receptor for protons. In the present study, we aimed to know whether OGR1 plays a role in insulin secretion and, if so, the manner in which it does. To this end, we created OGR1-deficient mice and examined insulin secretion activity in vivo and in vitro. OGR1 deficiency reduced insulin secretion induced by glucose administered ip, although it was not associated with glucose intolerance in vivo. Increased insulin sensitivity and reduced plasma glucagon level may explain, in part, the unusual normal glucose tolerance. In vitro islet experiments revealed that glucose-stimulated insulin secretion was dependent on extracellular pH and sensitive to OGR1; insulin secretion at pH 7.4 to 7.0, but not 8.0, was significantly suppressed by OGR1 deficiency and inhibition of Gq/11 proteins. Insulin secretion induced by KCl and tolbutamide was also significantly inhibited, whereas that induced by several insulin secretagogues, including vasopressin, a glucagon-like peptide 1 receptor agonist, and forskolin, was not suppressed by OGR1 deficiency. The inhibition of insulin secretion was associated with the reduction of glucose-induced increase in intracellular Ca2+ concentration. In conclusion, the OGR1/Gq/11 protein pathway is activated by extracellular protons existing under the physiological extracellular pH of 7.4 and further stimulated by acidification, resulting in the enhancement of insulin secretion in response to high glucose concentrations and KCl.

scholarly journals L41Q polymorphism of the G protein coupled receptor kinase 5 is associated with left ventricular apical ballooning syndrome

2009 ◽  
Vol 12 (1) ◽  
pp. 13-16 ◽  
Author(s):  
Letizia Spinelli ◽  
Valentina Trimarco ◽  
Serena Di Marino ◽  
Marina Marino ◽  
Guido Iaccarino ◽  
...  
Keyword(s):  
G Protein ◽  
Apical Ballooning ◽  
Left Ventricular ◽  
Apical Ballooning Syndrome ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Cardiac β-Adrenoceptor Desensitization Due to Increased β-Adrenoceptor Kinase Activity in Chronic Uremia

2002 ◽  
Vol 13 (1) ◽  
pp. 117-124
Author(s):  
Kirsten Leineweber ◽  
Ingrid Heinroth-Hoffmann ◽  
Klaus Pönicke ◽  
Getu Abraham ◽  
Bernd Osten ◽  
...  
Keyword(s):  
Right Ventricular ◽  
G Protein ◽  
Kinase Activity ◽  
Left Ventricular ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Noradrenaline Content ◽  
Baroreflex Control ◽  
Noradrenaline Transporter ◽  
G Protein Coupled

ABSTRACT. Patients with chronic renal failure develop an autonomic dysfunction with impaired baroreflex control and attenuated cardiovascular β-adrenoceptor response to noradrenaline. In rats that underwent 5/6-nephrectomy (SNX), cardiac β-adrenoceptor responsiveness was reduced as well. Therefore, the aim of this study was to further investigate the mechanism underlying cardiac β-adrenoceptor desensitization in SNX rats. For this purpose, right and left ventricular β-adrenoceptor density, activity of the G-protein–coupled receptor kinase, and activity and density of the neuronal noradrenaline transporter (uptake1) were assessed in SNX rats. Seven weeks after SNX, rats had developed left heart hypertrophy. Plasma creatinine, urea, and noradrenaline levels were significantly increased; left and right ventricular noradrenaline content was significantly decreased when compared with sham-operated control rats. In these SNX rats, left, but not right, ventricular β-adrenoceptor density was significantly reduced, and membrane-associated G-protein–coupled receptor kinase activity was significantly increased compared with sham-operated rats. Although right and left ventricular activity of uptake1 was unchanged, the neuronal noradrenaline transporter density was significantly reduced in both ventricles of SNX versus sham-operated rats. An increase in left ventricular G-protein–coupled receptor kinase activity, possibly triggered by enhanced cardiac noradrenaline release, might be responsible for the decrease in left ventricular β-adrenoceptor responsiveness in SNX rats.

G protein-coupled receptor 120 signaling regulates ghrelin secretion in vivo and in vitro

2014 ◽  
Vol 306 (1) ◽  
pp. E28-E35 ◽  
Author(s):  
Zhi Gong ◽  
Makoto Yoshimura ◽  
Sayaka Aizawa ◽  
Reiko Kurotani ◽  
Jeffrey M. Zigman ◽  
...  
Keyword(s):  
G Protein ◽  
Cell Lines ◽  
G Protein Coupled Receptor ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Expression Levels ◽  
Ghrelin Secretion ◽  
G Protein Coupled

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is produced predominantly in the stomach. It has been reported that endogenous ghrelin levels are increased by fasting and decreased immediately after feeding and that fasting-induced ghrelin release is controlled by the sympathetic nervous system. However, the mechanisms of plasma ghrelin decrement after feeding are poorly understood. Here, we studied the control of ghrelin secretion using ghrelin-producing cell lines and found that these cells express high levels of mRNA encoding G-protein coupled receptor 120 (GPR120). Addition of GW-9508 (a GPR120 chemical agonist) and α-linolenic acid (a natural ligand for GPR120) inhibited the secretion of ghrelin by ∼50 and 70%, respectively. However, the expression levels of preproghrelin and ghrelin O-acyltransferase (GOAT) mRNAs were not influenced by GW-9508. In contrast, the expression levels of prohormone convertase 1 were decreased significantly by GW-9508 incubation. Moreover, we observed that the inhibitory effect of GW-9508 on ghrelin secretion was blocked by a small interfering RNA (siRNA) targeting the sequence of GPR120. Furthermore, pretreatment with GW-9508 blocked the effect of the norepinephrine (NE)-induced ghrelin elevation in ghrelin cell lines. In addition, we showed that GW-9508 inhibited ghrelin secretion via extracellular signal-regulated kinase activity in ghrelin cell lines. Finally, we found that GW-9508 decreased plasma ghrelin levels in mice. These results suggest that the decrease of ghrelin secretion after feeding is induced partially by long-chain fatty acids that act directly on gastric GPR120-expressing ghrelin cells.

scholarly journals α-Actinin is a potent regulator of G protein-coupled receptor kinase activity and substrate specificity in vitro

FEBS Letters ◽  
2000 ◽  
Vol 473 (3) ◽  
pp. 280-284 ◽  
Author(s):  
Jennifer L.R. Freeman ◽  
Julie A. Pitcher ◽  
Xiaolin Li ◽  
Vann Bennett ◽  
Robert J. Lefkowitz
Keyword(s):  
Substrate Specificity ◽  
G Protein ◽  
Kinase Activity ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

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

Hypertension ◽  
2020 ◽  
Vol 76 (5) ◽  
pp. 1625-1636 ◽  
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.

scholarly journals G Protein-coupled Receptor Kinase 2–mediated Phosphorylation of Ezrin Is Required for G Protein-coupled Receptor–dependent Reorganization of the Actin Cytoskeleton

2005 ◽  
Vol 16 (7) ◽  
pp. 3088-3099 ◽  
Author(s):  
Sarah H. Cant ◽  
Julie A. Pitcher
Keyword(s):  
G Protein ◽  
Phosphorylation Site ◽  
Rho Kinase ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Glutathione S Transferase ◽  
Membrane Ruffling ◽  
Gpcr Activation ◽  
G Protein Coupled

G protein-coupled receptor kinase 2 (GRK2) phosphorylates and desensitizes activated G protein-coupled receptors (GPCRs). Here, we identify ezrin as a novel non-GPCR substrate of GRK2. GRK2 phosphorylates glutathione S-transferase (GST)-ezrin, but not an ezrin fusion protein lacking threonine 567 (T567), in vitro. These results suggest that T567, the regulatory phosphorylation site responsible for maintaining ezrin in its active conformation, represents the principle site of GRK2-mediated phosphorylation. Two lines of evidence indicate that GRK2-mediated ezrin-radixinmoesin (ERM) phosphorylation serves to link GPCR activation to cytoskeletal reorganization. First, in Hep2 cells muscarinic M1 receptor (M1MR) activation causes membrane ruffling. This ruffling response is ERM dependent and is accompanied by ERM phosphorylation. Inhibition of GRK2, but not rho kinase or protein kinase C, prevents ERM phosphorylation and membrane ruffling. Second, agonist-induced internalization of the β2-adrenergic receptor (β2AR) and M1MR is accompanied by ERM phosphorylation and localization of phosphorylated ERM to receptor-containing endocytic vesicles. The colocalization of internalized β2AR and phosphorylated ERM is not dependent on Na+/H+ exchanger regulatory factor binding to the β2AR. Inhibition of ezrin function impedes β2AR internalization, further linking GPCR activation, GRK activity, and ezrin function. Overall, our results suggest that GRK2 serves not only to attenuate but also to transduce GPCR-mediated signals.

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