scholarly journals G Protein-Coupled Receptor Kinase 2 Mediates Endothelin-1-Induced Insulin Resistance via the Inhibition of Both Gαq/11 and Insulin Receptor Substrate-1 Pathways in 3T3-L1 Adipocytes

2005 ◽  
Vol 19 (11) ◽  
pp. 2760-2768 ◽  
Author(s):  
Isao Usui ◽  
Takeshi Imamura ◽  
Jennie L. Babendure ◽  
Hiroaki Satoh ◽  
Juu-Chin Lu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
G Protein ◽  
Kinase Activity ◽  
Insulin Receptor Substrate ◽  
Glut4 Translocation ◽  
G Protein Coupled Receptor ◽  
Endothelin 1 ◽  
G Protein Coupled

Abstract G protein-coupled receptor kinases (GRKs) regulate seven-transmembrane receptors (7TMRs) by phosphorylating agonist-activated 7TMRs. Recently, we have reported that GRK2 can function as a negative regulator of insulin action by interfering with G protein-q/11 α-subunit (Gαq/11) signaling, causing decreased glucose transporter 4 (GLUT4) translocation. We have also reported that chronic endothelin-1 (ET-1) treatment leads to heterologous desensitization of insulin signaling with decreased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and Gαq/11, and decreased insulin-stimulated glucose transport in 3T3-L1 adipocytes. In the current study, we have investigated the role of GRK2 in chronic ET-1-induced insulin resistance. Insulin-induced GLUT4 translocation was inhibited by pretreatment with ET-1 for 24 h, and we found that this inhibitory effect was rescued by microinjection of anti-GRK2 antibody or GRK2 short interfering RNA. We further found that GRK2 mediates the inhibitory effects of ET-1 by two distinct mechanisms. Firstly, adenovirus-mediated overexpression of either wild-type (WT)- or kinase-deficient (KD)-GRK2 inhibited Gαq/11 signaling, including tyrosine phosphorylation of Gαq/11 and cdc42-associated phosphatidylinositol 3-kinase activity. Secondly, ET-1 treatment caused Ser/Thr phosphorylation of IRS-1 and IRS-1 protein degradation. Overexpression of KD-GRK2, but not WT-GRK2, inhibited ET-1-induced serine 612 phosphorylation of IRS-1 and restored activation of this pathway. Taken together, these results suggest that GRK2 mediates ET-1-induced insulin resistance by 1) inhibition of Gαq/11 activation, and this effect is independent of GRK2 kinase activity, and 2) GRK2 kinase activity-mediated IRS-1 serine phosphorylation and degradation.

scholarly journals Regulation of the Epithelial Na+ Channel by the RH Domain of G Protein-coupled Receptor Kinase, GRK2, and Gαq/11

2011 ◽  
Vol 286 (22) ◽  
pp. 19259-19269 ◽  
Author(s):  
Il-Ha Lee ◽  
Sung-Hee Song ◽  
Craig R. Campbell ◽  
Sharad Kumar ◽  
David I. Cook ◽  
...  
Keyword(s):  
G Protein ◽  
Kinase Activity ◽  
Receptor Activation ◽  
Na Channel ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Α Subunits

The G protein-coupled receptor kinase (GRK2) belongs to a family of protein kinases that phosphorylates agonist-activated G protein-coupled receptors, leading to G protein-receptor uncoupling and termination of G protein signaling. GRK2 also contains a regulator of G protein signaling homology (RH) domain, which selectively interacts with α-subunits of the Gq/11 family that are released during G protein-coupled receptor activation. We have previously reported that kinase activity of GRK2 up-regulates activity of the epithelial sodium channel (ENaC) in a Na+ absorptive epithelium by blocking Nedd4-2-dependent inhibition of ENaC. In the present study, we report that GRK2 also regulates ENaC by a mechanism that does not depend on its kinase activity. We show that a wild-type GRK2 (wtGRK2) and a kinase-dead GRK2 mutant (K220RGRK2), but not a GRK2 mutant that lacks the C-terminal RH domain (ΔRH-GRK2) or a GRK2 mutant that cannot interact with Gαq/11/14 (D110AGRK2), increase activity of ENaC. GRK2 up-regulates the basal activity of the channel as a consequence of its RH domain binding the α-subunits of Gq/11. We further found that expression of constitutively active Gαq/11 mutants significantly inhibits activity of ENaC. Conversely, co-expression of siRNA against Gαq/11 increases ENaC activity. The effect of Gαq on ENaC activity is not due to change in ENaC membrane expression and is independent of Nedd4-2. These findings reveal a novel mechanism by which GRK2 and Gq/11 α-subunits regulate the activity ENaC.

scholarly journals The Biased G-Protein-Coupled Receptor Agonism Bridges the Gap between the Insulin Receptor and the Metabolic Syndrome

2018 ◽  
Vol 19 (2) ◽  
pp. 575 ◽  
Author(s):  
Iryna Liauchonak ◽  
Fady Dawoud ◽  
Yatin Riat ◽  
Bessi Qorri ◽  
Manpreet Sambi ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Receptor ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
The Metabolic Syndrome ◽  
G Protein Coupled

scholarly journals G-protein-coupled receptor kinase activity in human heart failure: Effects of β-adrenoceptor blockade

2005 ◽  
Vol 66 (3) ◽  
pp. 512-519 ◽  
Author(s):  
K LEINEWEBER ◽  
P ROHE ◽  
A BEILFUS ◽  
C WOLF ◽  
H SPORKMANN ◽  
...  
Keyword(s):  
Heart Failure ◽  
G Protein ◽  
Human Heart ◽  
Kinase Activity ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Human Heart Failure ◽  
G Protein Coupled

scholarly journals G-protein-coupled Receptor Rhodopsin Regulates the Phosphorylation of Retinal Insulin Receptor

2007 ◽  
Vol 282 (13) ◽  
pp. 9865-9873 ◽  
Author(s):  
Ammaji Rajala ◽  
Robert E. Anderson ◽  
Jian-Xing Ma ◽  
Janis Lem ◽  
Muayyad R. Al-Ubaidi ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
G Protein ◽  
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.

Effect of GTP gamma S on insulin binding and tyrosine phosphorylation in liver membranes and L6 muscle cells

1990 ◽  
Vol 258 (1) ◽  
pp. C99-C108 ◽  
Author(s):  
E. Burdett ◽  
G. B. Mills ◽  
A. Klip
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
G Protein ◽  
G Proteins ◽  
Plasma Membranes ◽  
Kinase Activity ◽  
Muscle Cells ◽  
Permeabilized Cells ◽  
L6 Muscle Cells ◽  
Gamma S

Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), a specific activator of G proteins, did not change the Kd nor total binding of [125I]insulin in plasma membranes from rat liver. Insulin did not alter GTP gamma 35S binding nor polypeptide ADP ribosylation in crude and plasma membranes catalyzed either intrinsically or by cholera toxin. In L6 muscle cells, insulin caused tyrosine phosphorylation of a polypeptide of Mr 160,000. Cell electroporation enabled testing of G protein action in this cellular system. Phosphorylation of the Mr 160,000 polypeptide in these permeabilized cells was insulin and ATP dependent but other small molecules or ionic gradients were not essential. The reaction could not be mimicked by the G protein agonist GTP gamma S nor inhibited by the G protein antagonist guanosine 5'-O-(2-thiodiphosphate) (GDP beta S). However, GTP gamma S effectively decreased insulin-mediated phosphorylation of this polypeptide. This suggests that the tyrosine kinase activity of the insulin receptor can be modulated by G protein agonists. It is concluded that cross talk between the insulin receptor and G proteins could not be demonstrated in isolated membranes by strategies that detect interactions between beta-adrenergic receptors and G proteins. In contrast, in permeabilized cells, G protein-mediated regulation of the insulin receptor kinase activity could be detected.

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