Information on EC 2.7.11.16 - G-protein-coupled receptor kinase

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The expected taxonomic range for this enzyme is: Mammalia

EC NUMBER
COMMENTARY hide
2.7.11.16
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RECOMMENDED NAME
GeneOntology No.
G-protein-coupled receptor kinase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + [G protein-coupled receptor] = ADP + [G protein-coupled receptor]phosphate
show the reaction diagram
ATP + [G-protein-coupled receptor] = ADP + [G-protein-coupled receptor] phosphate
show the reaction diagram
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SYSTEMATIC NAME
IUBMB Comments
ATP:[G-protein-coupled receptor] phosphotransferase
Requires G-protein for activation and therefore belongs to the family of G-protein-dependent receptor kinases (GRKs). All members of this enzyme subfamily possess a highly conserved binding site for 1-phosphatidylinositol 4,5-bisphosphate. (cf. EC 2.7.11.14, rhodopsin kinase and EC 2.7.11.15, beta-adrenergic-receptor kinase).
CAS REGISTRY NUMBER
COMMENTARY hide
127407-08-3
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + a G protein-coupled receptor
ADP + a phosphorylated G protein-coupled receptor
show the reaction diagram
ATP + activated form of G protein-coupled receptors
ADP + phosphorylated G protein-coupled receptors
show the reaction diagram
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-
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ATP + alpha-synuclein
ADP + phosphorylated alpha-synuclein
show the reaction diagram
ATP + alpha1-adrenergic receptor
ADP + alpha1-adrenergic receptor phosphate
show the reaction diagram
GRK5 is also active with alpha1-adrenergic receptors. GRK5 activity, but not GRK2 activity, toward alpha1-adrenergic receptors can lead to transactivation of the tyrosine kinase receptor for epidermal growth factor in myocytes, cf. EC 2.7.11.15
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-
?
ATP + ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
ATP + beta 2-adrenergic receptor
ADP + phosphorylated beta 2-adrenergic receptor
show the reaction diagram
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
show the reaction diagram
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desensitization of the receptor by GRK4, GRK5, and GRK6
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-
?
ATP + BLT1 receptor
ADP + phosphorylated BLT1 receptor
show the reaction diagram
ATP + central M2 muscarinic receptor
ADP + phosphorylated central M2 muscarinic receptor
show the reaction diagram
ATP + CXCR4 receptor
ADP + phosphorylated CXCR4 receptor
show the reaction diagram
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
ATP + G-protein-coupled receptor
ADP + phosphorylated G-protein-coupled receptor
show the reaction diagram
ATP + protein
ADP + phosphoprotein
show the reaction diagram
major autophosphorylation sites are Ser484 and Thr485
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-
?
ATP + protein p105
ADP + phosphorylated protein p105
show the reaction diagram
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
ATP + rhodopsin
ADP + rhodopsin phosphate
show the reaction diagram
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cf. EC 2.7.11.14, rhodopsin is also a substrate of GRK5
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-
?
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor] phosphate
show the reaction diagram
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor]phosphate
show the reaction diagram
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GRK4-6
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-
?
ATP + [dopamine D1 receptor]
ADP + [dopamine D1 receptor]phosphate
show the reaction diagram
ATP + [follicle-stimulating hormone receptor]
ADP + [follicle-stimulating hormone receptor]phosphate
show the reaction diagram
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GRK4-6
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-
?
ATP + [G protein-coupled receptor]
ADP + [G protein-coupled receptor]phosphate
show the reaction diagram
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GRK4-6
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-
?
ATP + [G-protein-coupled receptor]
ADP + [G-protein-coupled receptor]phosphate
show the reaction diagram
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-
-
-
?
ATP + [luteinizing hormone/chorionic gonadotropin receptor]
ADP + [luteinizing hormone/chorionic gonadotropin receptor]phosphate
show the reaction diagram
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GRK4-6
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-
?
ATP + [M2 muscarinic receptor]
ADP + [M2 muscarinic receptor]phosphate
show the reaction diagram
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GRK4-6
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-
?
ATP + [M3 muscarinic acetylcholine receptor]
ADP + phospho-[M3 muscarinic acetylcholine receptor]
show the reaction diagram
ATP + [rhodopsin]
ADP + [rhodopsin]phosphate
show the reaction diagram
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GRK4-6
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-
?
ATP + [TSH receptor]
ADP + [TSH receptor]phosphate
show the reaction diagram
nucleophosmin 1 + ATP
phosphorylated nucleophosmin 1 + ADP
show the reaction diagram
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-
-
-
?
p53 + ATP
phosphorylated-p53 + ADP
show the reaction diagram
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-
-
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?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + a G protein-coupled receptor
ADP + a phosphorylated G protein-coupled receptor
show the reaction diagram
ATP + alpha-synuclein
ADP + phosphorylated alpha-synuclein
show the reaction diagram
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GRK5 phosphorylates Ser-129 of alpha-synuclein at the plasma membrane and induces translocation of phosphorylated alpha-synuclein to the perikaryal area, GRK5 promotes alpha-linolenic acid-induced oligomerization of alpha-synuclein, alpha-synuclein phosphorylation by GRK5 plays a crucial role in the pathogenesis of sporadic Parkinson's disease, sPD
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-
?
ATP + ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
show the reaction diagram
-
desensitization of the receptor by GRK4, GRK5, and GRK6
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-
?
ATP + BLT1 receptor
ADP + phosphorylated BLT1 receptor
show the reaction diagram
ATP + central M2 muscarinic receptor
ADP + phosphorylated central M2 muscarinic receptor
show the reaction diagram
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desensitization of the receptor by GRK5, GRK5 regulates pulmmonary responses by activation of the airway receptor, but does not regulate the peripheral cardiac muscarinic receptors
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-
?
ATP + CXCR4 receptor
ADP + phosphorylated CXCR4 receptor
show the reaction diagram
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
ATP + G-protein-coupled receptor
ADP + phosphorylated G-protein-coupled receptor
show the reaction diagram
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leading to receptor endocytosis
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-
?
ATP + protein p105
ADP + phosphorylated protein p105
show the reaction diagram
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?
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
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-
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?
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor] phosphate
show the reaction diagram
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GRK5 plays a distinctive role in the phosphorylation of the beta2AR
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?
ATP + [dopamine D1 receptor]
ADP + [dopamine D1 receptor]phosphate
show the reaction diagram
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GRK4 constitutively phosphorylates active and inactive receptor, in the latter case diminishing stimulation of the receptor by dopamine, phosphorylation reduces receptor desensitization and internalization, followed by reduced cAMP accumulation
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?
ATP + [G protein-coupled receptor]
ADP + [G protein-coupled receptor]phosphate
show the reaction diagram
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GRK4-6
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-
?
ATP + [G-protein-coupled receptor]
ADP + [G-protein-coupled receptor]phosphate
show the reaction diagram
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-
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-
?
ATP + [M3 muscarinic acetylcholine receptor]
ADP + phospho-[M3 muscarinic acetylcholine receptor]
show the reaction diagram
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GRK6 plays a major role in specific M3 muscarinic acetylcholine receptor regulation
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?
ATP + [TSH receptor]
ADP + [TSH receptor]phosphate
show the reaction diagram
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GRK4-6, receptor activation
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?
additional information
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
actin
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actinin
alpha-actinin
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Ca2+
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inhibits GRK5
Ca2+/calmodulin
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inhibit GRK5 with an IC50 of 40-50 nM, inhibition mechanism via inducing inhibitory autophosphorylation and blocking of membrane association
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Calmodulin
caveolin
GRK2ct
carboxylterminal portion of GRK2
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heparin
RKIP
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RNA aptamer C13
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development and synthesis of a highly specific RNA aptamer C13 that potently inhibits GRK2, EC 2.7.11.15, and GRK5, inhibitor secondary structure, overview
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additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
arrestins
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arrestins modulate the enzyme activity having a regulatory role, regulation of arrestins, overview
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isoproterenol
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stimulates the phosphorylation activity of GRK5 by10-15fold at 0.001 mM
methacholine
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stimulation of M3 muscarinic acetylcholine receptor phosphorylation is reversible by atropine
phosphatidylinositol 4,5-bisphosphate
Phospholipids
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activate GRK5
additional information
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00004 - 0.00005
Ca2+/calmodulin
Mus musculus
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inhibit GRK5 with an IC50 of 40-50 nM, inhibition mechanism via inducing inhibitory autophosphorylation and blocking of membrane association
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0.00008
Calmodulin
Homo sapiens
P32298
reaction of isoenzyme GRK4alpha with rhodopsin, IC50: 80 nM
0.000079
RNA aptamer C13
Homo sapiens
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inhibition of GRK5
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7
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assay at
7.4
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assay at
8
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
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assay at room temperature
37
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assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
spermatogonia cell line GC-1 spg
Manually annotated by BRENDA team
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enriched in GRK2 and GRK5
Manually annotated by BRENDA team
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intestinal epithelial cell line
Manually annotated by BRENDA team
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primary cells
Manually annotated by BRENDA team
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highly expressed
Manually annotated by BRENDA team
high activity
Manually annotated by BRENDA team
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neuroblastoma cell line, contains no GRK5
Manually annotated by BRENDA team
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airway, GRK5
Manually annotated by BRENDA team
GRK4gamma is the only detectable isoform in human sperm
Manually annotated by BRENDA team
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prepared without lymphocytic infiltrations in the tumor, GRKs expression patterns, moderate expression level of GRK4
Manually annotated by BRENDA team
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GRK5
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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association of GRK6 with the cell membrane is mediated in part by the palmitoylation of cysteine residues that lie in a C-terminal region
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Manually annotated by BRENDA team
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GRK5 co-localizes with gamma-tubulin, centrin, and pericentrin in centrosomes. The centrosomal localization of GRK5 is observed predominantly at interphase and although its localization is not dependent on microtubules, it can mediate microtubule nucleation of centrosome
Manually annotated by BRENDA team
additional information
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
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2 * 66050, recombinant acetylated, full-length, palmitoylation-deficient GRK6, mass spectrometry
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
lipoprotein
phosphoprotein
additional information
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
GRK2 by gel filtration from Sf9 cells
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partial purification of GRK5 from HEK-293 cell membranes, separation from GRK2 and GRK6, overview
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recombinant GST-tagged GRK5 from insect Sf9 cells by ion exchange and heparin affinity chromatography
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recombinant isozymes mGRK6-A, mGRK6-B, and mGRK-C from Sf9 insect cells by sequential gel filtration and heparin affinity chromatography
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
co-expression of isozyme GRK4gamma and dopamine D1 receptor in HEK-293 cells leads to phosphorylation of the receptor by GRK4, this effect is not seen with isozyme GRK4beta and GRK4delta
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co-expression of rat thyrotropin receptor with GRK4, GRK5, and GRK6 in HEK-293 cells, receptor phosphorylation occurs with GRK5 and GRK6
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co-overexpression of GRK5 with MEF2 receptor leads to increased MEF2 activity in myocytes
expressed in BAEC cells and HEK-293 cells
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expression of GRK4gamma in 293T cells, which are devoid of endogenous GRK4gamma
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expression of GRK6 in both Spodoptera frugiperda Sf9 and Trichoplusia ni High5 insect cells as a soluble, palmitoylation-deficient mutant in which three potential palmitoylation sites, located at Cys561, Cys562, and Cys565, are converted to Ser
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expression of GST-tagged GRK5 in Spodoptera frugiperda Sf9 cells using the baculovirus transfection method
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expression of isoforms mGRK6-A, mGRK6-B, mGRK-C, and mGRK-D in Spodoptera frugiperda Sf9 cells via baculovirus infection system, transient expression of isoforms mGRK6-A, mGRK6-B, mGRK-C, and mGRK-D in COS-7 cells, recombinant isoforms mGRK6-A, mGRK6-B, and mGRK-C are membrane-associated, recombinant isoform mGRK6-D is inactive and located in the nucleus
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expression of kinase-dead GRK4 mutant in HEK-293 cells
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gene encoding GRK5 with SM22alpha promoter for construction of transgenic mice expressing the enzyme in vascular smooth muscle
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gene GRK5, co-expression with human alpha-synuclein in HEK-293 cells and co-localization in the plasma membrane, functional co-expression of GRK5 and alpha-synuclein in primary cortical neurons from the cerebral cortex of fetal mice
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GRK4, DNA and amino acid sequence determination of polymorphisms, genotyping of American twins
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GRK4, DNA and amino acid sequence determination of polymorphisms, genotyping of Han Chinese individuals
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stable overexpression of wild-type and K215R mutant GRK6 in SH-SY5Y neuroblastoma cells via adenovirus infection system
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transient overexpression of wild-types and dominant negative mutants of GRK5 and GRK6 in COS-7 cells
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transient overexpression of wild-types and dominant negative mutants of GRK5 and GRK6 in NG108-15 mouse neuroblastoma x rat glioma hybrid cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
GRK2 is increased in expression and activity in lymphocytes and vascular smooth muscle in human hypertension
parvalbumin-positive interneurons express more of GRK2 and less of arrestin-2 than medium spiny neurons
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A486V
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naturally occuring functional polymorphism, the mutation leads to increased GRK4 activity and phosphorylation of dopamine receptors, phenotype
C561S/C562S/C565S
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site-directed mutagenesis, mutation of palmitoylation sites, the mutant protein retains its ability to phosphorylate rhodopsin, albeit with a 5fold higher Km and 2fold lower Vmax compared with those of wild-type GRK6
F527D
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site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
I165E
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site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
I165E/F527D
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site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
I39E
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site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
I39E/I165E
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site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
K216M/K217M
K220R
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kinase-dead mutant
R65L/A142V/A486V
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co-expression in CHO cells with the dopamine D1 receptor causes enhanced desensitization and agonist-independent phosphorylation of the receptor
K215R
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inactive dominant negative mutants of GRK5 or GRK6, overexpression of the GRK5 mutant in myometrial cells does not influence beta-adrenergic receptor sensitivity, while overexpression of GRK6 mutant leads to a 70% increase in isoproterenol-stimulated beta-adrenergic signaling via the beta-adrenergic receptor
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
diagnostics
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GRK5 levels in heart and peripheral lymphocytes correlate well, therefore the lymphocytic enzyme level might be a very suitable marker for determining the sympathetic drive to heart failure during clinical course and treatment of human congestive heart failure patients
medicine
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inhibition of GRK2 activity in osteoblasts as therapeutic strategy for increasing bone mass