ライフサイエンスコーパス: GRK2

1 ough release of G protein receptor kinase 2 (GRK2).

2 such as G protein-coupled receptor kinase 2 (GRK2).

3 on with G protein-coupled receptor kinase 2 (GRK2).

4 tor, which is facilitated by the GPCR kinase Grk2.

5 e the specific role of Gq-protein-binding by GRK2.

6 n inhibitor with more modest selectivity for GRK2.

7 expression, and the cognate kinases GRK1 and GRK2.

8 atients were evaluated for I5LO1, PEBP1, and GRK2.

9 endothelin signaling, which is regulated by GRK2.

10 of TGR5 interaction with beta-arrestin 2 and GRK2.

11 ated though a kinase-independent activity of GRK2.

12 expression of GRKInh, a peptide inhibitor of GRK2.

13 te whether the fish homologs of GRK2 and -5, Grk2/3 and Grk5, also have unique, complementary, or com

14 he beta2AR in ASM and the ability to exploit GRK2/3 functional domains to render ASM hyporesponsive t

15 ehydrochloride), to study the involvement of GRK2/3 in acute agonist-induced MOPr desensitization.

16 ovary-intact female mice with the selective GRK2/3 inhibitor, Compound 101, made females equally sen

17 GRK2/3 knockdown or expression of the GRK2 C terminus ca

18 2/3 were stably expressed, or siRNA-mediated GRK2/3 knockdown was performed, in human ASM cultures, a

19 The Grk2/3 loss-of-function embryos were rescued by this app

20 actile state, we assessed the specificity of GRK2/3 regulation of procontractile and relaxant G-prote

21 nd morphine-treated animals, suggesting that GRK2/3 remained active.

22 A loss of Grk2/3 results in dilated atria and hypoplastic ventricl

23 t although this seems to be the case for the GRK2/3 subfamily, GRK5/6 effectively phosphorylate inact

24 Functional domains of GRK2/3 were stably expressed, or siRNA-mediated GRK2/3 k

25 G protein-coupled receptor kinases 2 and 3 (GRK2/3) cooperated during agonist-induced phosphorylatio

26 cal inhibition of G-protein receptor kinase (GRK2/3) with compound 101 blocked acute desensitization.

27 In the case of Grk2/3, the progenitor decrease was confined to a subset

28 o clarify the potential utility of targeting GRK2/3-mediated desensitization as a means of manipulati

29 dels is G protein-coupled receptor kinase-2 (GRK2), a kinase originally discovered to be involved in

30 n show that selective recruitment applies to GRK2, a biologically relevant GPCR regulator, through di

31 GRK2, a G protein-coupled receptor kinase, plays a criti

32 1 week post-I/R in cardiomyocyte-restricted GRK2 ablated mice (also post-I/R) still demonstrated sig

33 In isolated muscle mechanics testing, GRK2 ablation caused a significant decrease in the speci

34 bryos with systemic or endothelium-selective Grk2 ablation had marked vascular malformations involvin

35 th activated fibroblast- or myocyte-specific GRK2 ablation-each initiated after myocardial ischemia-r

36 These two classes of compounds bind to the GRK2 active site in a similar configuration but contain

37 As such, levels of GRK2 activity in the heart directly correlate with cardi

38 energic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 lead

39 equently, therapeutic strategies that target GRK2 activity, not expression, may be more effective for

40 G-protein coupled receptor kinase 2 (GRK2; ADRBK1, BARK1) is most known as a regulator of G-p

41 Furthermore, increased expression of GRK2 after cardiac insult exacerbates injury and speeds

42 be partially rescued by the deletion of one Grk2 allele.

43 However, GRK2 also has other functions.

44 vels of G protein-coupled receptor kinase 2 (GRK2), an important negative modulator of both G protein

45 GRK2 and -5 belong to different subfamilies and function

46 to investigate whether the fish homologs of GRK2 and -5, Grk2/3 and Grk5, also have unique, compleme

47 inhibitor, was identified as an inhibitor of GRK2 and co-crystallized in the active site.

48 t therapies targeted at balancing nociceptor GRK2 and EPAC1 levels have promise for the prevention an

49 Conversely, the dual-specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibit

50 G258747, which has nanomolar potency against GRK2 and excellent selectivity over other kinases.

51 hibitor, 14as, with an IC50 of 30 nM against GRK2 and greater than 230-fold selectivity over other GR

52 brane-permeable, small-molecule inhibitor of GRK2 and GRK3, Takeda compound 101 (Cmpd101; 3-[[[4-meth

53 exhibited nanomolar IC50 values against both GRK2 and GRK5 and good selectivity against other closely

54 GRK2 and GRK5 are overexpressed in the failing heart and

55 en that increased expression and activity of GRK2 and GRK5 contribute to the loss of contractile rese

56 In summary, we found that GRK2 and GRK5 control cardiac function as well as morpho

57 Moreover, these MR-dependent GRK2 and GRK5 non-canonical activities appear to involve

58 The two most widely expressed GRKs (GRK2 and GRK5) play a role in cardiovascular disease and

59 ween phosphorylation of the same receptor by GRK2 and GRK5, demonstrating preference for the latter.

60 Both GRK2 and GRK5, the predominant GRKs expressed in the hea

61 nduced betaAR desensitization is mediated by GRK2 and is independent of Gbetagamma, uncovering a hith

62 flox)/cre recombinase) and overexpression of GRK2 and its regulator of G protein signaling homology (

63 th a prolongation of the interaction between GRK2 and the M3-ACh receptor and enhanced arrestin recru

64 Our data demonstrate a role for GRK2 (and potentially also GRK3) in agonist-induced MOPr

65 G protein-coupled receptor kinases 2 (GRK2) and 5 (GRK5) are fundamental regulators of cardiac

66 ch involves 15LO1/PEBP1 interactions to free GRK2, and allows it to phosphorylate (and desensitize) b

67 l muscle physiology and points to a role for GRK2 as a modulator of contractile properties in skeleta

68 Thus, we identify GRK2 as a potential molecular link between inflammation

69 eral of the hallmarks of cancer puts forward GRK2 as an oncomodifier, able to modulate carcinogenesis

70 ntified G protein-coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein.

71 GRK2 associated with PEBP1 after 10 minutes of ISO in as

72 ed PKA scaffolding significantly reduces DOR-GRK2 association at the plasma membrane and consequently

73 into SECs isolated from Cav1-deficient mice, GRK2 association with CAV1 was evident, whereas transduc

74 r, the mechanism that maintains constitutive GRK2 association with DOR is unknown.

75 Protein kinase A (PKA) phosphorylation of GRK2 at Ser-685 targets it to the plasma membrane.

76 es demonstrated that both Galpha(q)/PKC- and GRK2/beta-arrestin1-dependent V(1A)R signaling were capa

77 c2 cells mediates protective signaling via a GRK2/beta-arrestin1/ERK1/2-dependent mechanism that lead

78 We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1

79 Pharmacologic inhibition of GRK2 by the clinically approved antidepressant, serotoni

80 Inhibition of GRK2 by the dominant-negative GRK2-K220R did not affect

81 GRK2/3 knockdown or expression of the GRK2 C terminus caused a significant ( approximately 30-

82 Finally, transgenic expression of the GRK2 C terminus in murine ASM enabled approximately 30-5

83 traction of murine tracheal rings expressing GRK2 C terminus was also assessed.

84 GRK2 C-terminal expression did not affect signaling by m

85 Under conditions of GRK2 C-terminal expression, beta-agonist inhibition of m

86 maleimide, HCl, bisindolylmaleimide X, HCl), GRK2 [C-terminal GRK2 peptide overexpression and small i

87 Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MA

88 Higher levels of GRK2 can impair beta-adrenergic receptor-mediated inotro

89 , it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of myocytes and exert G

90 ased in injured SECs, resulting in increased GRK2-CAV1 interaction and decreased eNOS activity.

91 phorylation facilitates CAV1 scaffolding and GRK2-CAV1 interaction, thus clustering eNOS within a com

92 istinct conformation of the kinase domain of GRK2 compared with previous complexes with paroxetine an

93 l structure of this compound in complex with GRK2 confirmed the predicted interactions.

94 These data demonstrate that GRK2 contributes to proliferation and survival of these

95 of connections with other cellular proteins, GRK2 contributes to the modulation of basic cellular fun

96 The up- or down-regulation of GRK2 correlates with several pathological disorders.

97 tion of G-protein-coupled receptor kinase 2 (GRK2) could counteract the disturbed substrate metabolis

98 ith reduced binding affinity toward Galphaq [GRK2(D110A)] and Gbetagamma [GRK2(R587Q)] were used to d

99 Mice with GRK2 deficiency in D2R-expressing neurons also exhibited

100 The GRK2 deficiency in developing murine B cells leads to a

101 Furthermore, blocking S1PR1 signaling in the GRK2-deficient B cells partially corrected their poor re

102 Here we show that select GRK2-deficient mice display hyperactivity, hyposensitivi

103 main mechanism implicated in fasting-induced GRK2 degradation in the liver in vivo.

104 on of a G protein-coupled receptor kinase 2 (GRK2)-dependent beta(2) AR-G(i) -ERK1/2 cascade.

105 n of the GRK2 N terminus or kinase-dead holo-GRK2 diminished ( approximately 30-70%) both PI hydrolys

106 and dominant-negative approaches reveal that GRK2 directly phosphorylates and activates Mst2.

107 Further, the GRK2-DN transgene dramatically accelerates oncogene-init

108 egative G protein-coupled receptor kinase 2 (GRK2-DN) transgene diminishes AR and AR target gene expr

109 Moreover, decreased endothelial Grk2 dosage accelerated tumor growth in mice, along with

110 Our study suggests that GRK2 downregulation is a relevant event in the tumoral a

111 induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimick

112 f atypical protein kinase C zeta, leading to GRK2-driven Galphas inactivation.

113 y, preventing full downregulation of hepatic GRK2 during fasting using adenovirus-driven overexpressi

114 In summary, GRK2 enforces AR-dependence in the prostate, and the los

115 to favor vasoconstriction in the absence of GRK2 expression and that this leads to the age-dependent

116 We found that silencing GRK2 expression caused ~50% decrease in antigen-induced

117 Treating mice lacking GRK2 expression in their B cells with an S1PR1 antagonis

118 GRK2 expression is increased in hypertension and this fa

119 exercise capacity was not altered in MLC-Cre:GRK2(fl/fl) mice compared with wild-type controls.

120 onist, was significantly enhanced in MLC-Cre:GRK2(fl/fl) mice; mechanistically, this seems to be due

121 -specific GRK2 knock-out (KO) mouse (MLC-Cre:GRK2(fl/fl)) to gain a better understanding of the role

122 mediated GRK2 knockdown, GRK2 gene deletion (GRK2(flox/flox)/cre recombinase) and overexpression of G

123 (Gbeta) bind to DDB1 and that Gbeta2 targets GRK2 for ubiquitylation by the DDB1-CUL4A-ROC1 ubiquitin

124 -dependence in the prostate, and the loss of GRK2 function in prostate tumors accelerates disease pro

125 1, CCG257284, and CCG258748) in complex with GRK2-Gbetagamma Comparison of these structures with thos

126 ed lentiviral shRNA-mediated GRK2 knockdown, GRK2 gene deletion (GRK2(flox/flox)/cre recombinase) and

127 alpha proteins and multiple protein kinases [GRK2, GRK3, GRK5, GRK6 and protein kinase C (PKC)].

128 GRK2 has not been implicated in medulloblastoma biology.

129 Inducible ablation of GRK2 in activated fibroblasts (i.e., myofibroblasts) pos

130 further protection in mice with ablation of GRK2 in activated fibroblasts alone.

131 d, focusing on recently discovered roles for GRK2 in cardiomyocyte metabolism and the effects that th

132 Recently, nonclassical roles for GRK2 in cardiovascular disease have been described, incl

133 gene knockout approach to selectively delete GRK2 in DA D1 receptor (D1R)-, DA D2 receptor (D2R)-, ad

134 s transformed environment promoted decreased GRK2 in ECs and human breast cancer vessels.

135 osphorylatively modified and desensitized by GRK2 in failing cardiomyocytes, contributing to post-MI

136 tization was unaffected, implying a role for GRK2 in MOPr desensitization.

137 relatively little is known about the role of GRK2 in skeletal muscle function and disease.

138 provides the first insights into the role of GRK2 in skeletal muscle physiology and points to a role

139 o gain a better understanding of the role of GRK2 in skeletal muscle physiology.

140 To elucidate the specific role of GRK2 in the brain dopamine (DA) system, we used a condit

141 siological fasting-induced downregulation of GRK2 in the liver is key for allowing complete glucagon-

142 indings reveal a cell-type-specific role for GRK2 in the regulation of normal motor behavior, sensiti

143 tion of G-protein coupled receptor kinase 2 (GRK2) in both mouse models.

144 n mice, reduced expression of GPCR kinase 2 (GRK2) in nociceptors promotes cAMP signaling to the guan

145 We suggest that a surface of GRK2, including Leu(4), Val(7), Leu(8), Val(11), and Ser

146 investigated the hypothesis that Gbetagamma-GRK2 inhibition and/or ablation after myocardial injury

147 he potential therapeutic role for Gbetagamma-GRK2 inhibition in limiting pathological myofibroblast a

148 anding of the therapeutic role of Gbetagamma-GRK2 inhibition in treating HF and the potential therape

149 Systemic small molecule Gbetagamma-GRK2 inhibition initiated 1 week post-I/R in cardiomyocy

150 Systemic small molecule Gbetagamma-GRK2 inhibition initiated 1 week post-I/R provided littl

151 Small molecule Gbetagamma-GRK2 inhibition initiated 1 week post-injury was cardiop

152 Thus, GRK2 inhibition is a novel approach that targets the dys

153 Thus, cardioprotective signaling induced by GRK2 inhibition is overlapping with tumor growth promoti

154 h and development, we analyzed the impact of GRK2 inhibition on cell growth and proliferation.

155 Transgenic modulation demonstrated that GRK2 inhibition or GRK6 overexpression enhanced degradat

156 Cardioprotective GRK2 inhibition required an intact ERK axis, which blunt

157 Finally, Gbetagamma-GRK2 inhibition significantly attenuated activation char

158 eutic potential of small molecule Gbetagamma-GRK2 inhibition, alone or in combination with activated

159 this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC50 of 30 nM against GRK2

160 laid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibito

161 , paroxetine, was previously identified as a GRK2 inhibitor.

162 vide insight into the further development of GRK2 inhibitors as drug candidates.

163 rticle reviews the most potent and selective GRK2 inhibitors that have been developed.

164 zation assay was used to test the ability of GRK2 inhibitors to impart efficacy on a GRK-dependent pr

165 photorelaxation, which is greatly reduced by GRK2 inhibitors.

166 ase-dead mutant in vivo, we demonstrate that GRK2 inhibits CFA-induced hyperalgesia in a kinase activ

167 Finally, we show that GRK2 inhibits Epac1-mediated sensitization of the mechan

168 In vitro, GRK2 inhibits Epac1-to-Rap1 signaling by phosphorylation

169 l-induced GRK2 phosphorylation enhanced CAV1-GRK2 interaction and reduced eNOS activity.

170 GRK2 is a G protein-coupled receptor kinase (GRK) that i

171 Because GRK2 is also indispensable for growth and development, w

172 omain, indicating that CAV1 interaction with GRK2 is inversely regulated by endothelin-1 and CAV1 sca

173 Collectively these findings demonstrate that GRK2 is localized to centrosomes and plays a central rol

174 orepinephrine concentration, suggesting that GRK2 is recruited to Gbetagamma and alpha(2A)AR with EC5

175 G-protein-coupled receptor kinase 2 (GRK2) is a G-protein-coupled receptor kinase that is ubi

176 G-protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase with an important fun

177 G-protein-coupled receptor kinase 2 (GRK2) is arising as one of such nodes.

178 cardial G protein-coupled receptor kinase-2 (GRK2) is upregulated in HF patients, causing dysfunction

179 GRK2-K220R (kinase dead) and GRK2-S670A (unphosphorylate

180 Inhibition of GRK2 by the dominant-negative GRK2-K220R did not affect the proliferation of cultured

181 immunodeficient mice, the dominant-negative GRK2-K220R or a GRK2-specific peptide inhibitor increase

182 optimized interactions with the hinge of the GRK2 kinase domain.

183 e generated a novel skeletal muscle-specific GRK2 knock-out (KO) mouse (MLC-Cre:GRK2(fl/fl)) to gain

184 toposide attenuated ERK phosphorylation, but GRK2 knockdown did not alter this effect.

185 e associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro

186 increased phosphorylation of AKT (S473) and GRK2 knockdown mitigated this increase.

187 Finally, cardiac-specific GRK2 knockdown restored the cardioprotective effect of a

188 Here we report that GRK2 knockdown slowed cell growth, diminished proliferat

189 utilized included lentiviral shRNA-mediated GRK2 knockdown, GRK2 gene deletion (GRK2(flox/flox)/cre

190 n- and etoposide-induced apoptosis caused by GRK2 knockdown.

191 m in vivo is completely prevented in cardiac Grk2 knockout mice (KO) and to a lesser extent in Grk5 K

192 Cardiac-specific GRK2 knockout virtually abolished post-MI AdipoR1 phosph

193 ulated pro-hypertrophic Akt signaling in the GRK2 KO skeletal muscle.

194 ggest that the selectivity of paroxetine for GRK2 largely reflects its lower affinity for adenine nuc

195 K2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors.

196 Increased GRK2 levels also correlate with the degree of cognitive

197 Moreover, altered GRK2 levels are starting to be reported in different tum

198 Importantly, myocardial GRK2 levels correlate with levels found in peripheral ly

199 We found that lower GRK2 levels in activated B cell-type diffuse large B cel

200 Reducing GRK2 levels in murine primary hepatocytes facilitates gl

201 Such downregulation of GRK2 levels is liver-specific and can be rapidly reverse

202 his study was to evaluate whether lymphocyte GRK2 levels predict clinical outcome in HF patients.

203 GRK2 levels showed an additional prognostic and clinical

204 e independent prognostic value of lymphocyte GRK2 levels was also confirmed for all-cause mortality.

205 epinephrine, serum NT-proBNP, and lymphocyte GRK2 levels, as well as clinical and instrumental variab

206 tivation status in heart failure influencing GRK2 levels.

207 haq enhances the extent and stability of the GRK2-M3-ACh receptor interaction, and that not only Gbet

208 These new roles of GRK2 suggest that GRK2 may be a nodal link in the myocyte, influencing bot

209 The independent prognostic value of blood GRK2 measurements in HF patients has never been investig

210 ition of phosphoinositide 3-kinase abolished GRK2-mediated betaAR phosphorylation and GRK2 recruitmen

211 nsitization involves at least two autonomous GRK2-mediated components: 1) a phosphorylation-independe

212 /11 signaling, as the consequence of reduced GRK2-mediated desensitization.

213 Therefore, we sought to determine whether GRK2-mediated DOR desensitization is directed by PKA via

214 ith obesity/metabolic syndrome, in which the GRK2-mediated signaling can be a potential therapeutic m

215 a-Adrenergic receptor kinase 1 (betaARK 1 or GRK2) mediates desensitization of photorelaxation, which

216 GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on

217 These data demonstrate that GRK2 modulates FcinRI signaling in mast cells via at lea

218 GRK2 mutants with reduced binding affinity toward Galpha

219 Expression of the GRK2 N terminus or kinase-dead holo-GRK2 diminished ( ap

220 GRK2 null animals exhibit embryonic lethality due to a s

221 compound, 12n (CCG-224406), had an IC50 for GRK2 of 130 nM, >700-fold selectivity over other GRK sub

222 The effect of GRK2 on cytokine generation does not require its catalyt

223 Here, we sought to determine the role of GRK2 on FcinRI signaling and mediator release in mast ce

224 inflammatory pain, we found that increasing GRK2 or decreasing EPAC1 inhibited chronic hyperalgesia.

225 GRK2 or GRK2-RH had no effect on antigen-induced phospho

226 Here we hypothesized that reduction of GRK2 or increased EPAC1 in dorsal root ganglion (DRG) ne

227 ng sensory neuron-specific overexpression of GRK2 or its kinase-dead mutant in vivo, we demonstrate t

228 Overexpression of GRK2 or its RH domain (GRK2-RH) enhanced antigen-induced

229 possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1.

230 Reciprocally, GRK2 overexpression attenuated apoptosis induced by thes

231 Moreover, GRK2 overexpression enhanced CXCR4 internalization, via

232 poR1 phosphorylation, whereas virus-mediated GRK2 overexpression significantly phosphorylated AdipoR1

233 Interactions of GRK2, PEBP1, and 15LO1 were detected by means of immunop

234 isindolylmaleimide X, HCl), GRK2 [C-terminal GRK2 peptide overexpression and small interfering RNA (s

235 f ISO in association with low phosphorylated GRK2 (pGRK2) levels.

236 Finally, isoproterenol-induced GRK2 phosphorylation enhanced CAV1-GRK2 interaction and

237 erminal intracellular AdipoR1 region) as the GRK2 phosphorylation sites.

238 s were measured using ELISA, and beta2AR and GRK2 phosphorylation was measured using Western blotting

239 alone paralleled by increases in beta2AR and GRK2 phosphorylation.

240 via the G-protein-coupled receptor kinase 2 (GRK2)/PI3K signaling pathway.

241 ed alveolar epithelial fluid transport via a GRK2/PI3K-dependent mechanism.

242 ated alveolar epithelial fluid transport via GRK2/PI3K-dependent mechanisms.

243 activity, GRK2 Ser-685 phosphorylation, and GRK2 plasma membrane targeting than controls.

244 GRK2 plays an important role in the maintenance of heart

245 inhibition in living cells, confirming that GRK2 predominantly drives internalization of MOR in the

246 ondrial G protein-coupled receptor kinase 2 (GRK2) pro-death activity and GRK5 pro-hypertrophic actio

247 Lymphocyte GRK2 protein levels can independently predict prognosis

248 ro brain natriuretic peptide, and lymphocyte GRK2 protein levels were independent predictors of CV mo

249 ociation from Gbeta2, leading to increase of GRK2 protein.

250 toward Galphaq [GRK2(D110A)] and Gbetagamma [GRK2(R587Q)] were used to determine the specific role of

251 hed GRK2-mediated betaAR phosphorylation and GRK2 recruitment on TNFalpha.

252 tization or cardiac dysfunction showing that GRK2 recruitment to the betaAR is Gbetagamma independent

253 Wildtype GRK2 reversed the increase in cisplatin- and etoposide-i

254 lls via at least two mechanisms.One involves GRK2-RH and modulates tyrosine phosphorylation of Syk, a

255 GRK2 or GRK2-RH had no effect on antigen-induced phosphorylation

256 Overexpression of GRK2 or its RH domain (GRK2-RH) enhanced antigen-induced mast cell degranulatio

257 of G protein signaling homology (RH) domain (GRK2-RH).

258 GRK2-K220R (kinase dead) and GRK2-S670A (unphosphorylated, constitutively active) con

259 Previously, we discovered two classes of GRK2-selective inhibitors, one stemming from GSK180736A,

260 Site-directed mutagenesis revealed that GRK2 Ser-685 phosphorylation drives the association of G

261 m AKAP-knock-out mice had less PKA activity, GRK2 Ser-685 phosphorylation, and GRK2 plasma membrane t

262 dy, we show that the B cell-specific loss of GRK2 severely disrupts B cell trafficking and immune cel

263 aroxetine (PX), recapitulated the effects of GRK2 silencing with dose- and time-dependent IGF1R downr

264 Only clathrin recognizes and stabilizes GRK2-specific beta-arrestin-1 conformations.

265 mice, the dominant-negative GRK2-K220R or a GRK2-specific peptide inhibitor increased tumor mass.

266 In the course of a GRK2 structure-based drug design campaign, one inhibitor

267 , demonstrates increased potency against the GRK2 subfamily and favorable pharmacokinetic parameters

268 G258208 also showed high selectivity for the GRK2 subfamily in a kinome panel of 104 kinases.

269 We have synthesized a new GRK2 subfamily-selective inhibitor, CCG258747, which has

270 These new roles of GRK2 suggest that GRK2 may be a nodal link in the myocyt

271 from cisplatin that was similar to wildtype GRK2, suggesting that this protection may be mediated th

272 ted by cAMP 1 (EPAC1) by G protein kinase 2 (GRK2) suppresses Epac1-to-Rap1 signaling, thereby inhibi

273 n this respect, GRK4alpha is more similar to GRK2 than GRK6.

274 on with G-protein-coupled receptor kinase-2 (GRK2) that also post-translationally modifies eNOS.

275 itor of G protein-coupled receptor kinase 2 (GRK2) that improves cardiac performance in live animals.

276 ole for G-protein-coupled receptor kinase 2 (GRK2) that renders DOR analgesically incompetent at the

277 er-based assay to monitor the recruitment of GRK2 to activated alpha(2A)-adrenergic receptors (alpha(

278 The recruitment of GRK2 to activated receptors is well known to be mediated

279 re additionally crystallized in complex with GRK2 to give insights into the structural determinants o

280 of the new inhibitors were crystallized with GRK2 to give molecular insights into the binding and kin

281 role of Galphaq in efficient recruitment of GRK2 to M3-ACh receptors.

282 ma membrane targeting and phosphorylation of GRK2 to maintain DOR analgesic incompetence in periphera

283 e of IL-13 plus ISO (10 minutes), binding of GRK2 to PEBP1 decreased, whereas 15LO1 binding and pGRK2

284 The prognostic value of GRK2 to predict cardiovascular (CV) death and all-cause

285 only Gbetagamma but also Galphaq can target GRK2 to the membrane.

286 GRK2 up-regulation can lead to changes in the insulin si

287 GRK2 up-regulation can worsen cardiac ischemia; furtherm

288 s showed significant betaAR desensitization, GRK2 upregulation, and recruitment to the betaAR complex

289 demonstrate here, that genetic knockdown of GRK2 using a small hairpin (sh) RNA results in altered v

290 High level transfection of GRK2 variants influenced signaling of ETA-WT and ETA-6PD

291 etine exhibits up to 50-fold selectivity for GRK2 versus other GRKs.

292 When either GRK2 was increased in vivo by viral-based gene transfer

293 urthermore, interactions between Galphaq and GRK2 were associated with a prolongation of the interact

294 n induced a sustained decrease in nociceptor GRK2, whereas priming with the PKCepsilon agonist Psieps

295 review, classical and nonclassical roles for GRK2 will be discussed, focusing on recently discovered

296 off-pathway conformational states unique to GRK2 will likely be key for the development of even more

297 ss the role of Galphaq on the interaction of GRK2 with activated Gq-protein-coupled receptors.

298 85 phosphorylation drives the association of GRK2 with plasma membrane-associated DOR.

299 regulator, through discrete interactions of GRK2 with receptors or with G protein beta-gamma subunit

300 ET)-based assays to study the interaction of GRK2 with the M3-acetylcholine (M3-ACh) receptor as well