ライフサイエンスコーパス: GRK1

1 GRK1 has also been reported to be present in retinal con

2 GRK1 phosphorylates photoactivated rhodopsin, initiating

3 GRK1, GRK2, and GRK5, which represent the three known GR

4 G-Protein receptor kinase 1 (GRK1) ("rhodopsin kinase") is necessary for the inactiva

5 phat2), G-protein-coupled receptor kinase 1 (GRK1) and guanylate cyclase 1 (GC1) has been suggested t

6 G-protein-coupled receptor (GPCR) kinase 1 (GRK1) phosphorylation of light-activated rhodopsin (R*)

7 its and G-protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the Rp2h(-/-

8 sport of transducin, and rhodopsin kinase 1 (GRK1), also prenylated substrates of RCE1, was unaffecte

9 nown as G protein-coupled receptor kinase 1 (GRK1), is a component of the light adaptation pathway ex

10 ed by G-protein-dependent receptor kinase 1 (GRK1).

11 kinase [G-protein-coupled receptor kinase 1 (GRK1)] and subsequent binding of arrestin.

12 psin by G protein-coupled receptor kinase 1 (GRK1, or rhodopsin kinase) is critical for the deactivat

13 transducin and G-protein receptor kinase-1 (GRK1) accumulated on large punctate structures within th

14 se 6 (PDE6) and G-protein receptor kinase-1 (GRK1) levels.

15 nd cone G-protein coupled receptor kinase-1 (GRK1).

16 Dark-adapted GRK1 -/- animals generated cone-driven ERGs having satur

17 Additionally, GRK1 excess abolished the acceleration of saturated resp

18 We show that although GRK1 is required for the timely inactivation of mouse co

19 n complex with peptides derived from D2R and GRK1 reveals that the differential recognition is facili

20 In contrast, GRK7 and GRK1 are coexpressed in monkey and human cones, suggesti

21 ted species-specific differences in GRK7 and GRK1 expression in cones.

22 interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor outer segme

23 phosphodiesterase 6alpha' (PDE6alpha'), and GRK1 (G-protein-coupled receptor kinase 1; opsin kinase)

24 cone phototransduction through recoverin and GRK1 are not well understood.

25 nes share the same isoforms of recoverin and GRK1, and photoactivation also triggers a calcium declin

26 rongly labeled cone outer segments with anti-GRK1 and anti-GRK7.

27 or L/M opsin were strongly labeled with anti-GRK1, whereas outer segments positive for S opsin showed

28 gainst other closely related kinases such as GRK1 and PKA.

29 Because GRK1 (rhodopsin kinase), the GRK that mediates rhodopsin

30 Lack of both GRK1 and GRK7 in S cones of patients with ESCS results i

31 , which was observed in all nucleotide-bound GRK1 structures.

32 Using our recent structure of bovine GRK1 as a guide, we generated mutants of solvent-exposed

33 but does not occur when GRK7 is present but GRK1 is deficient in Oguchi disease.

34 phosphorylation of rhodopsin is mediated by GRK1.

35 cin activation, rhodopsin phosphorylation by GRK1 and high affinity arrestin-1 binding only requires

36 f GRK1 lacking the N-terminal region (DeltaN-GRK1), peptides that directly interact with ATP were not

37 ts positive for S opsin showed no detectable GRK1 reactivity.

38 In cone cells, either GRK1, GRK7, or both, depending on the species, are specu

39 Among these enzymes, GRK1 (rhodopsin kinase) is involved in phototransduction

40 hat both rod and cone photoreceptors express GRK1.

41 ined from several strains of mice expressing GRK1 at 0.3- to 3-fold the wild-type levels.

42 indicate that both recombinant farnesylated GRK1 and geranylgeranylated GRK7 co-precipitate with a g

43 ch lacks consensus phosphorylation sites for GRK1, GRK2, and GRK3.

44 membrane-associated proteins (e.g. Galphat2, GRK1 and GC1) continue to have trafficking problems.

45 sured in mice having null mutations of GRK1 (GRK1 -/-) cone-driven electroretinographic (ERG) respons

46 ested the ability of each of the known GRKs (GRK1-6) to phosphorylate and rescue the sequestration of

47 RK6 >> GRK2 (IC50 approximately 2 microM) >> GRK1.

48 utant and rescue its sequestration; however, GRK1 was totally ineffective in rescuing either the phos

49 udies in vitro, we predicted that Ser(21) in GRK1 would be phosphorylated by cAMP-dependent protein k

50 s with Oguchi disease caused by mutations in GRK1, and 1 normal control.

51 he recoverin and calmodulin-binding sites in GRK1 do not overlap, recoverin-GRK1 interaction is inhib

52 contrast with the known effect of increasing GRK1 expression in rods.

53 r proteins in vitro, including opsin kinase (GRK1/GRK7) and rab8.

54 y showed that farnesylated rhodopsin kinase (GRK1) and prenylated rod PDE6 catalytic subunits partial

55 interact with farnesylated rhodopsin kinase (GRK1) and that prenylation is essential for this interac

56 reduced concentrations of rhodopsin kinase (GRK1) and/or arrestin1 influenced the kinetics and varia

57 opsin is phosphorylated by rhodopsin kinase (GRK1) as efficiently as rhodopsin in the native disc mem

58 um-dependent inhibition of rhodopsin kinase (GRK1) by recoverin.

59 To determine the role of rhodopsin kinase (GRK1) in phosphorylating this opsin and to test whether

60 how that overexpression of rhodopsin kinase (GRK1) increases phosphorylation of the GPCR rhodopsin bu

61 six crystal structures of rhodopsin kinase (GRK1), revealing not only three distinct nucleotide-bind

62 h antibodies against cone opsins and kinases GRK1 and GRK7 in postmortem normal and ESCS retinal tiss

63 surface expression, and the cognate kinases GRK1 and GRK2.

64 amily of G protein-coupled receptor kinases (GRK1-GRK7).

65 contrast, the unique N-terminally localized GRK1 site for recoverin had no clearly defined structura

66 GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro.

67 Absence of GRK1 greatly prolongs the photoreceptors' light response

68 m for retinal degeneration in the absence of GRK1, suggesting a second, not previously recognized rol

69 the Rpe65(-/-) mouse is due to the action of GRK1 and is neuroprotective.

70 Interestingly, analysis of GRK1 and GRK5, which lack a pleckstrin homology domain,

71 Finally, the deletion of GRK1 triggered retinal degeneration in Grk1(-/-) mice af

72 in the light-dependent dephosphorylation of GRK1.

73 The effect of GRK1 expression level on the function of mouse rods was

74 A model incorporating an effect of GRK1 on light-activated PDE* decay rate can satisfactori

75 conditioning flash, the cone-driven ERGs of GRK1 -/- animals recovered 30-50 times more slowly than

76 Altering the expression of GRK1 from 0.3- to 3-fold that in wild-type rods had litt

77 Biasing the competition in favor of GRK1 revealed that rhodopsin remained active through muc

78 apped changes in the backbone flexibility of GRK1 as it binds to its two substrates, adenosine tripho

79 found that the conformational flexibility of GRK1 was reduced in the presence of either Mg(2+).ATP or

80 In a truncated form of GRK1 lacking the N-terminal region (DeltaN-GRK1), peptid

81 hat rods and cones, express the same form of GRK1.

82 responses converge and become independent of GRK1 levels for flashes activating more than approximate

83 Notably, increasing the expression level of GRK1 accelerated the dim flash response shut off but had

84 dark state, likely due to reduced levels of GRK1 in rod outer segments.

85 tion using mice expressing various levels of GRK1 or lacking recoverin.

86 from mouse rods expressing various levels of GRK1 to evaluate how their function is modulated by rhod

87 levels and abnormal retinal localizations of GRK1 and rod transducin subunits (GNAT1 and GNB1) in zeb

88 A current proposed model of GRK1 activation involves the binding of activated rhodop

89 we measured in mice having null mutations of GRK1 (GRK1 -/-) cone-driven electroretinographic (ERG) r

90 Overexpression of GRK1 increases the rate of Rh* phosphorylation and reduc

91 od cells, we propose that phosphorylation of GRK1 and GRK7 by PKA occurs in the dark, when cAMP level

92 Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK

93 on and dephosphorylation, phosphorylation of GRK1 by PKA is likely to be involved in light and dark a

94 se type 1 is required for phosphorylation of GRK1 on Ser(21).

95 To compare the biochemical properties of GRK1 and GRK7, we measured the K(m) and V(max) of these

96 rhodopsin (Rho*) to the N-terminal region of GRK1.

97 inus of the beta2AR is highly reminiscent of GRK1-mediated phosphorylation of rhodopsin.

98 To elucidate the potential role of GRK1 in cone opsin phosphorylation, we created Nrl and G

99 To examine the role of GRK1 in retinal cone signaling pathways, we measured in

100 To evaluate the role of GRK1 in rod light response decay, we have generated the

101 understanding of the physiological roles of GRK1 and GRK7 in human cone photoreceptors.

102 as a 19-amino acid N-terminal truncation of GRK1, also show decreased catalytic efficiency for pepti

103 eceptors also transcribe a splice variant of GRK1, which differs in its C-terminal region next to the

104 Taken together with data on GRK1 and GRK6, our data suggest that all three GRK subfa

105 2+).ATP, the influence of Rho* versus Rho on GRK1 dynamics was negligible.

106 , whereas in mice and rats, we detected only GRK1 in cones.

107 clusion was supported by the cloning of only GRK1 from cone-dominated chicken retina.

108 rs by using mouse models lacking rods and/or GRK1.

109 These results suggest that either GRK7 or GRK1 may participate in cone opsin desensitization, depe

110 s-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photore

111 Rhodopsin kinase (Rk or GRK1) is a photoreceptor-specific enzyme that mediates a

112 ansport of prenylated proteins, particularly GRK1 and cone PDE, to rod and cone outer segments, resul

113 ein kinase II, neither kinase phosphorylated GRK1 or GRK7.

114 nificantly elevated levels of phosphorylated GRK1 compared with light-adapted animals.

115 lyl cyclase type 1, levels of phosphorylated GRK1 were low in retinas from both dark- and light-adapt

116 ependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro

117 ding sites in GRK1 do not overlap, recoverin-GRK1 interaction is inhibited by calmodulin, most likely

118 In Pde6d(-/-) cone outer segments, GRK1 and cone PDE6alpha' were present at very low levels

119 rprisingly, none of the three GRK subgroups (GRK1, GRK2/3, and GRK4/5/6) shares even a single intron

120 tes are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated wit

121 Our observations argue that GRK1 is essential for normal deactivation of murine cone

122 presence of dibutyryl-cAMP, suggesting that GRK1 and GRK7 are physiologically relevant substrates.

123 d mutants of solvent-exposed residues in the GRK1 kinase domain that are conserved among GRKs but not

124 s a 310 helix-turn-310 helix, whereas in the GRK1 peptide complex it forms an alpha-helix.

125 ce on Ca(2+)/NCS-1, but only one copy of the GRK1 peptide binds.

126 30 of the N terminus, observed in one of the GRK1.(Mg2+)2.ATP structures.

127 s are produced in Rv(-/-) rods, in which the GRK1-binding protein recoverin has been genetically dele

128 human L/M cones can occur without GRK7 when GRK1 is present in ESCS, but does not occur when GRK7 is

129 igh degree of sequence conservation, whereas GRK1 and particularly GRK4 have accumulated amino acid c

130 erated the transgenic mouse RKS561L in which GRK1, which is normally present at only 2-3% of rhodopsi

131 While GRK1 (rhodopsin kinase) is inhibited by the photorecepto

132 the protein is relatively low compared with GRK1 (now called GRK1a), and GRK1b appears to have very

133 rhodopsin phosphorylation by competing with GRK1.

134 ned the atomic structure of its complex with GRK1, the most weakly inhibited GRK tested.