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 G Protein–Coupled Receptor Kinase-6 Interacts with Activator of G Protein Signaling-3 To Regulate CXCR2-Mediated Cellular Functions

2014 ◽  
Vol 192 (5) ◽  
pp. 2186-2194 ◽  
Author(s):  
Vandana Singh ◽  
Sandeep K. Raghuwanshi ◽  
Nikia Smith ◽  
Elizabeth J. Rivers ◽  
Ricardo M. Richardson
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Cellular Functions ◽  
G Protein Coupled

scholarly journals Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor

2020 ◽  
Vol 117 (28) ◽  
pp. 16346-16355 ◽  
Author(s):  
Amirhossein Mafi ◽  
Soo-Kyung Kim ◽  
William A. Goddard
Keyword(s):  
Side Effects ◽  
G Protein ◽  
Three Dimensional ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
G Protein Coupled Receptor ◽  
Intracellular Loop ◽  
Cytoplasmic Region ◽  
Gi Protein ◽  
G Protein Coupled

Agonists to the μ-opioid G protein-coupled receptor (μOR) can alleviate pain through activation of G protein signaling, but they can also induce β-arrestin activation, leading to such side effects as respiratory depression. Biased ligands to μOR that induce G protein signaling without inducing β-arrestin signaling can alleviate pain while reducing side effects. However, the mechanism for stimulating β-arrestin signaling is not known, making it difficult to design optimum biased ligands. We use extensive molecular dynamics simulations to determine three-dimensional (3D) structures of activated β-arrestin2 stabilized by phosphorylated μOR bound to the morphine and D-Ala2,N-MePhe4, Gly-ol]-enkephalin (DAMGO) nonbiased agonists and to the TRV130 biased agonist. For nonbiased agonists, we find that the β-arrestin2 couples to the phosphorylated μOR by forming strong polar interactions with intracellular loop 2 (ICL2) and either the ICL3 or cytoplasmic region of transmembrane (TM6). Strikingly, Gi protein makes identical strong bonds with these same ICLs. Thus, the Gi protein and β-arrestin2 compete for the same binding site even though their recruitment leads to much different outcomes. On the other hand, we find that TRV130 has a greater tendency to bind the extracellular portion of TM2 and TM3, which repositions TM6 in the cytoplasmic region of μOR, hindering β-arrestin2 from making polar anchors to the ICL3 or to the cytosolic end of TM6. This dramatically reduces the affinity between μOR and β-arrestin2.

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 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.

scholarly journals Regulation of G protein-coupled receptor kinase activity.

1994 ◽  
Vol 104 (3) ◽  
pp. 207-216 ◽  
Author(s):  
Tatsuya HAGA ◽  
Kazuko HAGA ◽  
Kimihiko KAMEYAMA ◽  
Hiroko NAKATA
Keyword(s):  
G Protein ◽  
Kinase Activity ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled
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