© 1997 American Heart Association, Inc.
Articles |
ß-Arrestin1 Knockout Mice Appear Normal but Demonstrate Altered Cardiac Responses to ß-Adrenergic Stimulation
From the Howard Hughes Medical Institute and the Department of Genetics, Harvard Medical School, Boston, Mass (D.A.C., M.C., J.G.S.); the Department of Medicine, Allegheny General Hospital and the Allegheny University of the Health Sciences, Pittsburgh, Pa (M.A.M.); the Endocrine Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (R.M.M.); the Allegheny University of the Health Sciences, Cardiovascular and Pulmonary Research Institute, Pittsburgh (S.F.V.); and the Brigham and Women's Hospital, Department of Medicine, and Howard Hughes Medical Institute, Boston (C.E.S.).
Correspondence to J.G. Seidman, Department of Genetics, Harvard Medical School, Alpert Building Room 533, 200 Longwood Ave, Boston, MA 02115. E-mail seidman{at}rascal.med.harvard.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Abstract ß-Arrestin1 knockout mice were studied to define the physiological role of ß-arrestin1 in the regulation of G protein–coupled receptors. ß-Arrestin1 is thought to be involved in the desensitization of many G protein–associated cell surface receptors, particularly ß-adrenergic receptors. Homozygous knockout mice are overtly normal. Resting cardiovascular parameters modulated by ß-adrenergic receptors such as heart rate, blood pressure, and left ventricular ejection fraction are not changed. However, homozygous mutants are more sensitive to ß-receptor agonist–stimulated increases in ejection fraction, consistent with a role of ß-arrestin1 in ß-adrenergic receptor desensitization. We conclude that ß-arrestin1 is important for in vivo G protein–coupled receptor desensitization and that this aspect of desensitization represents a mechanism for fine-tuning responses. However, ß-arrestin1 does not appear to be required for development or for other essential biological functions.
Key Words: ß-arrestin1 • knockout mice • desensitization • G protein–coupled receptor
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Arrestins are thought to bind G protein–coupled receptors that have been phosphorylated by G protein–coupled receptor kinases (GRKs). The association of arrestins with phosphorylated receptors blocks receptor interaction with heterotrimeric G proteins, resulting in signal termination. The combined action of these two groups of proteins is thought to mediate rapid desensitization of particular G protein–coupled receptors.1 In vitro GRK and arrestin effects are dependent on each other: neither protein alone can significantly terminate signal transduction.2 In addition to physically blocking receptor coupling with G proteins, ß-arrestin1 modulates agonist-promoted ß2-adrenergic receptor internalization (sequestration) in HEK 293 cells.3,4 In fact, ß-arrestin1 binds directly to clathrin and may act as an adapter to target phosphorylated ß2-adrenergic receptors to clathrin-coated vesicles.5 Although these data clearly demonstrate that the ß2-adrenergic receptor is regulated by ß-arrestin1 in vitro, there is no evidence that ß-arrestin1 is a physiological regulator of the receptor. Other reports suggest that ß-arrestin1 may regulate ß1-adrenergic receptors, M2-muscarinic receptors, and
1B-adrenergic receptors.6–8 ß-Arrestin1 is a member of a small protein family that consists of four proteins: arrestin, arrestin-C, ß-arrestin1, and ß-arrestin2.2,9–11 Arrestin and arrestin-C are expressed primarily in rod and cone cells in the visual system. ß-Arrestin1 and ß-arrestin2 are widely expressed. ß-Arrestin1 is usually more abundant than ß-arrestin2.12 The physiological roles of ß-arrestin1 and ß-arrestin2 are undefined.
Critical questions regarding the precise physiological role of particular arrestins have been hampered by the lack of reagents that specifically block arrestin action. We hypothesized that knockout mice lacking a particular arrestin would provide a valuable tool for studying the role of particular arrestins. Mice lacking ß-arrestin1 were created using gene targeting and blastocyst-mediated transgenesis. ß-Arrestin1–deficient mice have a normal life expectancy and by a variety of different parameters appear normal. However, the ß-arrestin1–deficient mice do demonstrate alterations of in vivo ß-adrenergic receptor responses compared with their wild-type littermates.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preparation of Targeting Construct
A fragment of the ß-arrestin1 gene was isolated from a custom Lambda Dash II 129/SvJ mouse genomic library (Stratagene Inc) using a bovine ß-arrestin1 cDNA probe. An 11-kb EcoRV fragment was inserted into a Bluescript SK II (+)–based plasmid (Stratagene Inc) containing the neomycin resistance gene (neor) under control of the phosphoglycerate kinase promoter.
Cell Culture and Blastocyst Injection
The C1 ES cell line13 was cultured on irradiated
mouse embryonic fibroblasts in supplemented DMEM with 500 U/mL ESGRO
(GIBCO Laboratories). Construct DNA (1 pmol) was linearized at the
unique Kpn I site and transfected by electroporation (125
µF, 400 V: Gene Pulser; Bio-Rad Laboratories) into
2.5x107 C1 cells. Cells surviving G418 (0.2 mg/mL
active, GIBCO Laboratories) were screened by Southern blot
analysis (Fig 1
). Targeted clones
were injected into C57BL/6 (Taconic, Germantown, NY) blastocysts (15
cells/embryo). Germ-line transmission by the resultant chimeric males
was determined by crossing with Black Swiss females (Taconic).
Heterozygous mutants were mated to produce the F2 generation. All
experiments were performed with mice in the mixed 129/SvJ and Black
Swiss background. Wild-type control animals were age- and sex-matched
sibs.
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Western Blot Analysis
Cytosolic proteins were separated using nonreducing sodium
dodecyl sulfate–polyacrylamide gel electrophoresis.
Western blot analysis was performed using the ECL detection
system (Amersham). The monoclonal antibody MabF4C1, which recognizes a
conserved arrestin domain, was generously provided by Dr Larry
Donoso.12,14
Adenylyl Cyclase Assay
Assays were performed as previously described,15
with some modifications. Briefly, crude membrane fractions were
prepared by homogenization of hearts, from 9- to
10-month-old male mice, in 20 mmol/L Tris (pH 7.6) and
5 mmol/L EDTA. Homogenates were
centrifuged at 800g for 10 minutes to remove nuclei.
The supernatant was centrifuged at 20 000g for 20
minutes. The pellet was resuspended in 75 mmol/L Tris (pH
7.6), 2 mmol/L EDTA, and 12.5 mmol/L
MgCl2 at a protein concentration of 1 mg/mL.
Reactions in triplicate contained approximately 20 mg of membrane
protein, 30 mmol/L Tris (pH 7.6), 0.8 mmol/L
EDTA, 5 mmol/L MgCl2 (approximately 4.0
mmol/L free MgCl2), 2.7 µmol/L
phosphoenolpyruvate, 50 mmol/L GTP, 100 mmol/L
cAMP, 120 mmol/L [-32P]ATP (0.3
µCi/tube), 20 U/mL myokinase, 4 U/mL pyruvate kinase, and
isoproterenol (0 to 30 mmol/L) or NaF (10
mmol/L). Tubes were incubated for 10 minutes at 37°C.
Reactions were terminated by the addition of 1 mL of a solution
containing 0.3 mmol/L cAMP (with approximately 10 000 cpm
of [3H]cAMP), 0.4 mmol/L ATP, and 1% SDS (pH
7.5). cAMP was isolated by sequential chromatography
with Dowex (AG 50W-X4) and neutral alumina (WN-3). Results are
expressed as a percentage of the NaF response.
In Vivo Determination of Ejection Fraction
All animal care was in accordance with institutional guidelines.
Experiments were performed as previously described.16
Briefly, adult male mice (approximately 1 year old and weighing 40 to
60 g) were anesthetized by
intraperitoneal injection with ketamine
(0.065 mg/g), acepromazine (0.002 mg/g), and xylazine
(0.013 mg/g) and allowed to breathe spontaneously. The chest was
shaved and the animal was positioned prone on a warmed (37°C) saline
bag stand-off suspended between two supports.
Echocardiography was performed from below the
stand-off using an Interspec Apogee X-200 ultrasonograph
(Interspec-ATL) with a 9-MHz annular array transducer. Short axis
M-mode measurements of left ventricular internal diameter
(LVID) were determined by averaging values from more than 3 beats using
the leading edge–to–leading edge convention adopted by the American
Society of Echocardiography.17 Left
ventricular ejection fraction (LVEF) was calculated by the
cubed method as follows:
LVEF=[(LVIDd)3-(LVIDs)3]/LVIDd3,
where d indicates diastolic and s indicates
systolic. Measurements were performed at baseline and during
intravenous infusion (via a previously placed jugular
catheter) of isoproterenol (0.05, 0.1, and 0.2 µg/kg per
minute for 5 minutes each). The total amount of infusate was less than
100 µL. Heart rate was measured continuously from an on-line ECG
acquired using subcutaneously placed needle electrodes.
In Vivo Determination of Blood Pressure and Heart Rate
Mean arterial blood pressures were monitored by
femoral artery catheterization18,19 in
conscious 3-month-old male mice. After anesthesia with
avertin (tribromoethyl alcohol and tertiary amyl alcohol), the femoral
artery was cannulated with drawn out PE-10 tubing. The cannula was then
exteriorized and secured to a swivel device, allowing mobility of the
animal. The cannula was attached to a Y-connector, with one arm going
to a presssure transducer and the second arm attached to an infusion
pump (1 µL/min dextrose/heparin). Animals were allowed to recover for
at least 24 hours before studies were performed.
Blood Chemistry
Blood was obtained by cardiac puncture following administration
of avertin. Serum and whole blood were submitted to the Tufts
Veterinary Diagnostic Laboratory for evaluation.
Flow Cytometry
Spleen cells were prepared from age-matched mice
(approximately 3 months old). Cells were stained with
fluorescent-labeled antibodies and subjected to flow cytometry
in a Cytofluorograf II (Becton Dickinson & Co).
Linkage Analysis
Linkage analysis was performed using Mapmaker 3.0.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Targeted Disruption of the ß-Arrestin1 Gene
A bacteriophage
clone (designated ßarr-1) was isolated from
a 129/SvJ mouse genomic bacteriophage library that encoded part of
the murine ß-arrestin1 gene. An internal portion of the murine
ß-arrestin1 gene was found on an 11-kb EcoRV fragment and
was used to make a targeting construct (Fig 1A
). Although the exact
intron/exon structure of the murine ß-arrestin1 gene was not
determined, hybridization with a bovine ß-arrestin1 cDNA confirmed
that the EcoRV fragment lacked the 5' and 3' end of the
coding region. The targeting construct was linearized at a unique
Kpn I site within the region of homology and introduced into
C1 ES cells by electroporation. ES cell clones surviving G418 selection
were screened for insertions in the endogenous
ß-arrestin1 gene by Southern blot analyses using an
"external" EcoRV fragment (Fig 1A). One of every 12
G418-resistant clones exhibited a novel 16.5-kb Ase
I fragment consistent with insertion of the entire vector into
the ß-arrestin1 locus (Fig 1A). Cells from one of the targeted lines
were injected into C57BL/6 blastocysts. Seven germ-line chimeric males
were identified by mating with wild-type Black Swiss females.
Heterozygous offspring were crossed to generate mice homozygous for the
ß-arrestin1 mutation (Arrb1-/-).
Arrb1-/-, Arrb1-/+, and Arrb1+/+
mice were characterized by Southern blot analysis of DNA from
the tail (Fig 1B). Homozygous Arrb1-/- mice were viable.
Localization of the ß-Arrestin1 Gene to Chromosome 7
Heterozygous Arrb1-/+ mice were derived from mating
between chimeric agouti male mice and Black Swiss females. The
Arrb1-/+ mice were also heterozygous at two coat color
loci, tyr (tyrosinase) and p (pink-eye
dilute), that are closely linked on chromosome 7 (Fig 2). Characterization of F2 mice, the
offspring of intercrosses between F1 Arrb1-/+ mice,
suggested that these coat color loci were linked to the ß-arrestin1
gene. That is, 14 of 15 albino F2 mice (homozygous at the
tyr locus) were also homozygous for the ß-arrestin1
mutation, demonstrating linkage rather than random association between
the tyr locus and the ß-arrestin1 gene. The
genotypes of 68 F2 mice were assessed at the two coat color
loci and at D7MIT40 (Fig 2 and Reference 2020 ).
Analysis of these genotypes using Mapmaker 3.0
indicated that the ß-arrestin1 gene was more likely
(P<.0001) to be located between tyr and
D7MIT40 than between tyr and p (Fig 2). Genotype data were consistent with the model that
the ß-arrestin1 gene is about 1.5 centimorgans from the
tyr locus (Fig 2).
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Absence of ß-Arrestin1 Protein in Homozygous
Arrb1-/- Mice
Northern blot and Western blot analyses were performed to
determine the effect of the ß-arrestin1 gene insertion on RNA and
protein expression. Heart and kidney RNAs from wild-type mice contained
a 7.5-kb ß-arrestin1 mRNA species (Fig 3A). However, no ß-arrestin1 mRNAs
were detected in any tissues derived from homozygous
Arrb1-/- mice (Fig 3A). Equivalent amounts of ß-actin
mRNA were detected in RNA samples from Arrb1-/- and
wild-type mice (Fig 3A, lower panel). The absence of ß-arrestin1
protein in homozygous mutants was verified by Western blot
analysis using a mouse monoclonal antibody against a conserved
domain of arrestin (Fig 3B). The 53-kD ß-arrestin1 band is
present in brain cytosol from wild-type mice and absent in
Arrb1-/- mice. Similar results were obtained with cytosol
preparations from the heart and with membrane preparations from these
tissues (data not shown). The anti-mouse secondary antibody used to
detect the primary antibody also recognized IgG in the protein samples
(migrating at greater than 100 kD in the nonreducing gel in Fig 3B),
demonstrating that equivalent amounts of protein were loaded in each
lane. Thus, the introduced mutation results in the complete ablation of
the ß-arrestin1 gene product.
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Characteristics of Arrb1-/- Mice
Adult Arrb1-/- mice appeared identical to wild-type
littermates. Male and female Arrb1-/- mice were fertile
and produced normal size litters. Hematoxylin and eosin staining of
fixed sections revealed no histological abnormalities
in heart, kidney, brain, intestine, spleen, and lung (data not shown).
Homozygous mutants kept for over 1.5 years showed no reduction in life
expectancy when compared with wild-type littermates.
The blood chemistry values obtained from Arrb1-/- mouse
blood were similar to those obtained from wild-type littermates (Table 1). Hemoglobin, hematocrit, white blood
cell counts, and red blood cell counts of Arrb1-/- and
wild-type littermates were indistinguishable (Table 1).
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High levels of ß-arrestin1 expression in spleen and
peripheral lymphocytes has led to the speculation that the
protein may modulate lymphocyte signaling.12,21 FACS
analysis of Arrb1-/- mouse lymphocytes was used
to screen for gross immune system defects. Spleen cells were isolated
from Arrb1-/- and wild-type littermates. The total number
of cells was similar for the two groups of animals:
Arrb1-/-, 5.5±0.5x107; wild-type,
5.2±0.3x107. A variety of antisera were chosen on the
basis of their ability to distinguish major classes of lymphocytes
(Table 2). No significant differences
were observed. Of particular note, normal numbers of B cells were
observed in Arrb1-/- spleens as indicated by staining
with anti-B220, anti-kappa light chain, and anti-IgM heavy chain. No
changes were observed in the number of T cells as indicated by staining
with the anti-thy1.1,1.2 antisera. Normal ß (H57) and 
(GL3)
T-cell subpopulations were also present. No change in the number of
macrophages (mac-1) was observed.
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Cardiovascular Characteristics of
Arrb1-/- Mice
ß-Adrenergic receptor function was investigated because of the
proposed role of ß-arrestin1 in adrenergic receptor signaling.
Coupling of the ß-adrenergic receptor to adenylyl cyclase was
assessed in heart membrane preparations from control and
Arrb1-/- mice. Isoproterenol dose-response curves were
not significantly different in wild-type and Arrb1-/-
heart membranes; no differences in Vmax or EC50
were observed (data not shown). The resting mean blood pressure
(114.3± 3.4 mm Hg, n=3; 117.8±1.1 mm Hg, n=4: mean±SEM)
and heart rate (603.3±44.1 bpm, n=3; 662.5±43.1 bpm, n=4: mean±SEM)
of conscious wild-type and Arrb1-/- mice were also
indistinguishable. Anesthetized mutant and wild-type mice had
the same basal heart rates and ejection fractions (Fig 4). There was no difference in the
isoproterenol-mediated increase in heart rate between the wild-type and
mutant mice except at the highest isoproterenol concentration (Fig 4B).
However, isoproterenol produced significantly greater increases in
ejection fraction in mutant mice at each isoproterenol concentration
than was produced in wild-type mice (Fig 4A).
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) and
wild-type (
) mice. A, Cardiac ejection fraction was assessed by
echocardiography in anesthetized mice both
in the absence and presence of increasing isoproterenol concentrations
(see "Materials and Methods"). B, Heart rate was monitored
simultaneously in the same animals (see "Materials and
Methods"). Each point is the mean±SEM for 6 wild-type and 5 mutant
mice. *P<.05 (Student's t test). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We demonstrate here that the ß-arrestin1 gene is on mouse chromosome 7, closely linked to the murine albino locus, and that ß-arrestin1–deficient mice are viable with no overt differences from wild-type littermates. ß-Arrestin1–deficient mice and wild-type littermates have indistinguishable life expectancy, fertility, blood chemistry, mean resting blood pressure, resting heart rate, and immune systems. ß-Arrestin1 is not essential for mouse development or viability. However, the cardiac response of ß-arrestin1–deficient mice to isoproterenol appears to be different from that of wild-type mice.
The absence of a severe phenotype in ß-arrestin1–deficient
mice was unexpected given the widespread expression of
ß-arrestin12,11,21 and its presumed modulatory role for
many G protein–coupled receptors.1 Knockout mice lacking
GRK2 (ß-adrenergic receptor kinase 1), another component of the
G-protein–signaling pathway, are not viable, demonstrating an
essential role for this pathway in mouse physiology.22
There is no ß-arrestin1 protein in the tissues of the
ß-arrestin1–deficient mouse (Fig 3B). Perhaps essential arrestin
functions in these mice are provided by ß-arrestin2. That is,
ß-arrestin1 and ß-arrestin2 are more than 75%
identical,11 so ß-arrestin2 might be induced in the
ß-arrestin1–deficient mouse to compensate for the absence of
ß-arrestin1. However, the monoclonal antibody MabF4C1 recognizes a
highly conserved amino acid sequence, DGVVLVD, present near the
amino terminus of rat and human arrestin, arrestin-C, ß-arrestin1,
and ß-arrestin2 and should recognize mouse
ß-arrestin2.12,14,23 The absence of ß-arrestin2
immunoreactivity in wild-type and mutant mice is consistent
with reports showing that ß-arrestin2 is much less abundant than
ß-arrestin1 in most tissues12 and suggests that there is
no compensatory induction of ß-arrestin2 in the
ß-arrestin1–deficient mice. A small increase of ß-arrestin2 might
not have been detected by this analysis. However, arrestins are
believed to function stoichiometrically. Thus, we suggest that a small
increase in ß-arrestin2 would not be able to compensate for the
complete lack of the more abundant ß-arrestin1.
In vitro studies suggest that the ß-adrenergic receptor is a likely
target of ß-arrestin1, although there is no direct in vivo data to
support this hypothesis. Basal, isoproterenol-stimulated, and
NaF-stimulated adenylyl cyclase activities were not altered in
Arrb1-/- heart membrane preparations (data not shown).
This observation suggests that there is no compensatory change in
ß-adrenergic receptor density, Gs abundance, or
coupling efficiency in the homozygous mutant mice. However, we
recognize that subtle changes in the signal transduction system due to
ß-arrestin1 deficiency might not have been detected by this assay.
In vivo differences between wild-type and mutant animals were evident.
ß-Arrestin1 modifies isoproterenol-induced increases in ejection
fraction as assessed by echocardiography in
anesthetized animals. Mice lacking ß-arrestin1 have a
significantly greater response than wild-type mice at each
isoproterenol concentration (Fig 4). This difference is not observed
for the isoproterenol-induced increase in heart rate, except at the
greatest isoproterenol concentration, suggesting that ß-arrestin1 is
a more important regulator of the inotropic effects of isoproterenol
than of its chronotropic effects. Although some
isoproterenol-stimulated responses were altered, resting heart rate and
blood pressure were not different between the two groups of mice. These
results are consistent with a current model of ß-arrestin1
action1 in which only agonist-activated receptors
are targets for ß-arrestin1 regulation during desensitization.
Although ß-arrestin1 probably functions in other tissues and in
physiological processes other than the inotropic
response to isoproterenol, it appears to have a negligible role in
maintaining basal sympathetic tone.
We have demonstrated an in vivo role for ß-arrestin1 in the regulation of G protein–coupled receptors. Although the protein is widely expressed, ß-arrestin1 is not required for development or for essential biological functions. ß-Arrestin1 knockout mice will provide a useful system for determining the receptor specificity of ß-arrestin1 and for identifying its role in other aspects of receptor desensitization such as receptor internalization. These studies also demonstrate the usefulness of ß-arrestin1 as a new therapeutic target: inhibition of ß-arrestin1 action could potentiate the effects of exogenous or endogenous activators of G protein–coupled receptors without producing gross deleterious effects.
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Acknowledgments |
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This work was supported by the Howard Hughes Medical Institute. We thank Dr Larry Donoso for providing us with the monoclonal antibody MabF4C1 and Juanita Campos-Torres for her assistance with the FACS analysis.
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Footnotes |
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This manuscript was sent to Laurence H. Kedes, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received June 17, 1997; accepted September 9, 1997.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Freedman NJ, Lefkowitz RJ. Desensitization of G protein-coupled receptors. Recent Prog Horm Res. 1996;51:319–351.
2.
Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz
RJ. ß-arrestin: a protein that regulates ß-adrenergic receptor
function. Science. 1990;248:1547–1550.
3.
Zhang J, Ferguson SSG, Barak LS, Menard L, Caron
MG. Dynamin and ß-arrestin reveal distinct mechanisms for G
protein-coupled receptor internalization. J Biol Chem. 1996;271:18302–18305.
4. Ferguson SS, Downey WER, Colapietro AM, Barak LS, Menard L, Caron MG. Role of ß-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science. 1996;271:363–366.[Abstract]
5. Goodman OB, Krupnick JG, Santini F, Gurevich VV, Penn RB, Gagnon AW, Keen JH, Benovic JL. ß-arrestin acts as a clathrin adapter in endocytosis of the ß2-adrenergic receptor. Nature. 1996;383:447–450.[Medline] [Order article via Infotrieve]
6.
Gurevich VV, Dion SB, Onorato JJ, Ptasienski J, Kim
CM, Sterne-Marr R, Hosey MM, Benovic JL. Arrestin interactions with G
protein-coupled receptors: direct binding studies of wild type and
mutant arrestins with rhodopsin, ß2-adrenergic, and
m2-muscarinic cholinergic receptors. J Biol
Chem. 1995;270:720–731.
7.
Diviani D, Lattion AL, Larbi N, Kunapuli P, Pronin A,
Benovic JL, Cotecchia S. Effect of different G protein-coupled receptor
kinases on phosphorylation and desensitization of the
1B-adrenergic receptor. J Biol Chem. 1996;271:5049–5058.
8.
Freedman NJ, Liggett SB, Drachman DE, Pei G, Caron MG,
Lefkowitz RJ. Phosphorylation and desensitization of
the human ß1-adrenergic receptor: involvement of G
protein-coupled receptor kinases and cAMP-dependent protein kinase.
J Biol Chem. 1995;270:17953–17961.
9. Yamaki K, Takahashi Y, Sakuragi S, Matsubara K. Molecular cloning of the S-antigen cDNA from bovine retina. Biochem Biophys Res Commun. 1987;142:904–910.[Medline] [Order article via Infotrieve]
10.
Craft CM, Whitmore DH, Wiechmann AF. Cone arrestin
identified by targeting expression of a functional family. J
Biol Chem. 1994;269:4613–4619.
11.
Attramadal H, Arriza JL, Aoki C, Dawson TM, Codina J,
Kwatra MM, Snyder SH, Caron MG, Lefkowitz RJ. ß-arrestin2, a novel
member of the arrestin/ß-arrestin gene family. J Biol
Chem. 1992;267:17882–17890.
12.
Sterne-Marr R, Gurevich VV, Goldsmith P, Bodine RC,
Sanders C, Donoso LA, Benovic JL. Polypeptide variants of ß-arrestin
and arrestin3. J Biol Chem. 1993;268:15640–15648.
13.
Hendrickson BA, Conner DA, Ladd DJ, Kendall D, Casanova
JE, Corthesy B, Max EE, Neutra MR, Seidman CE, Seidman JG. Altered
hepatic transport of immunoglobulin A in mice lacking the J chain.
J Exp Med. 1995;182:1905–1911.
14. Dua HS, Lee RH, Lolley RN, ßarrett JA, Abrams M, Forrester JV, Donoso LA. Induction of experimental autoimmune uveitis by the retinal photoreceptor cell protein, phosducin. Curr Eye Res. 1992;11:107–111.
15. Salomon Y. Adenylate cyclase assay. Adv Cyclic Nucl Res. 1979;10:35–55.[Medline] [Order article via Infotrieve]
16.
Iwase M, Bishop SP, Uechi M, Vatner DE, Shannon RP,
Kudej RK, Wight DC, Wagner TE, Ishikawa Y, Homcy CJ, Vatner SF. Adverse
effects of chronic endogenous sympathetic drive induced by
cardiac GS overexpression. Circ Res. 1996;78:517–524.
17.
Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations
regarding quantitation in M-mode echocardiography:
results of a survey of echocardiographic measurements.
Circulation. 1978;58:1072–1083.
18.
Steinhelper ME, Cochrane KL, Field LJ. Hypotension
in transgenic mice expressing atrial natriuretic factor
fusion genes. Hypertension. 1990;16:301–307.
19. Conrad KP, Brinck-Johnsen T, Gellai M, Valtin H. Renal autoregulation in chronically catheterized conscious rats. Am J Physiol. 1984;247:F229–F233.
20. Mouse Genome Database (MGD), Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, Maine. World Wide Web (URL:http//www.informatics.jax.org). 1997.
21.
Parruti G, Peracchia F, Sallese M, Ambrosini G, Masini
M, Rotilio D, De Blasi A. Molecular analysis of human
ß-arrestin1: cloning, tissue distribution, and regulation of
expression. Identification of two isoforms generated by alternative
splicing. J Biol Chem. 1993;268:9753–9761.
22.
Jaber M, Koch WJ, Rockman H, Smith B, Bond RA,
Sulik KK, Ross J Jr, Lefkowitz RJ, Caron MG, Giros B. Essential role of
ß-adrenergic receptor kinase 1 in cardiac development and function.
Proc Natl Acad Sci U S A. 1996;93:12974–12979.
23. National Center for Biotechnology (NCBI). World Wide Web (URL:http://www.ncbi.nlm.nih.gov/). 1997.
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M. D. Bruss, W. Richter, K. Horner, S.-L. C. Jin, and M. Conti Critical Role of PDE4D in {beta}2-Adrenoceptor-dependent cAMP Signaling in Mouse Embryonic Fibroblasts J. Biol. Chem., August 15, 2008; 283(33): 22430 - 22442. [Abstract] [Full Text] [PDF]
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V. V. Gurevich and E. V. Gurevich Rich Tapestry of G Protein-Coupled Receptor Signaling and Regulatory Mechanisms Mol. Pharmacol., August 1, 2008; 74(2): 312 - 316. [Abstract] [Full Text] [PDF]
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 S. K. Raghuwanshi, M. W. Nasser, X. Chen, R. M. Strieter, and R. M. Richardson Depletion of {beta}-Arrestin-2 Promotes Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer J. Immunol., April 15, 2008; 180(8): 5699 - 5706. [Abstract] [Full Text] [PDF]
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 L. Liu, R. L. Davis, and G. Roman Exploratory Activity in Drosophila Requires the kurtz Nonvisual Arrestin Genetics, March 1, 2007; 175(3): 1197 - 1212. [Abstract] [Full Text] [PDF]
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 K. Rajagopal, E. J. Whalen, J. D. Violin, J. A. Stiber, P. B. Rosenberg, R. T. Premont, T. M. Coffman, H. A. Rockman, and R. J. Lefkowitz beta-Arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes PNAS, October 31, 2006; 103(44): 16284 - 16289. [Abstract] [Full Text] [PDF]
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Y. Su, S. K. Raghuwanshi, Y. Yu, L. B. Nanney, R. M. Richardson, and A. Richmond Altered CXCR2 Signaling in {beta}-Arrestin-2-Deficient Mouse Models J. Immunol., October 15, 2005; 175(8): 5396 - 5402. [Abstract] [Full Text] [PDF]
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M. J. Lynch, G. S. Baillie, A. Mohamed, X. Li, C. Maisonneuve, E. Klussmann, G. van Heeke, and M. D. Houslay RNA Silencing Identifies PDE4D5 as the Functionally Relevant cAMP Phosphodiesterase Interacting with {beta}Arrestin to Control the Protein Kinase A/AKAP79-mediated Switching of the {beta}2-Adrenergic Receptor to Activation of ERK in HEK293B2 Cells J. Biol. Chem., September 30, 2005; 280(39): 33178 - 33189. [Abstract] [Full Text] [PDF]
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A. Palmitessa, H. A. Hess, I. A. Bany, Y.-M. Kim, M. R. Koelle, and J. L. Benovic Caenorhabditus elegans Arrestin Regulates Neural G Protein Signaling and Olfactory Adaptation and Recovery J. Biol. Chem., July 1, 2005; 280(26): 24649 - 24662. [Abstract] [Full Text] [PDF]
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 S. L. Ferrari, D. D. Pierroz, V. Glatt, D. S. Goddard, E. N. Bianchi, F. T. Lin, D. Manen, and M. L. Bouxsein Bone Response to Intermittent Parathyroid Hormone Is Altered in Mice Null for {beta}-Arrestin2 Endocrinology, April 1, 2005; 146(4): 1854 - 1862. [Abstract] [Full Text] [PDF]
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 J.-J. Boffa and W. J. Arendshorst Maintenance of Renal Vascular Reactivity Contributes to Acute Renal Failure during Endotoxemic Shock J. Am. Soc. Nephrol., January 1, 2005; 16(1): 117 - 124. [Abstract] [Full Text] [PDF]
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L. M. Bohn, L. A. Dykstra, R. J. Lefkowitz, M. G. Caron, and L. S. Barak Relative Opioid Efficacy Is Determined by the Complements of the G Protein-Coupled Receptor Desensitization Machinery Mol. Pharmacol., July 1, 2004; 66(1): 106 - 112. [Abstract] [Full Text] [PDF]
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 Q. Wang, J. Zhao, A. E. Brady, J. Feng, P. B. Allen, R. J. Lefkowitz, P. Greengard, and L. E. Limbird Spinophilin Blocks Arrestin Actions in Vitro and in Vivo at G Protein-Coupled Receptors Science, June 25, 2004; 304(5679): 1940 - 1944. [Abstract] [Full Text] [PDF]
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G. B. Bolger, A. McCahill, E. Huston, Y.-F. Cheung, T. McSorley, G. S. Baillie, and M. D. Houslay The Unique Amino-terminal Region of the PDE4D5 cAMP Phosphodiesterase Isoform Confers Preferential Interaction with {beta}-Arrestins J. Biol. Chem., December 5, 2003; 278(49): 49230 - 49238. [Abstract] [Full Text] [PDF]
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T. A. Kohout and R. J. Lefkowitz Regulation of G Protein-Coupled Receptor Kinases and Arrestins During Receptor Desensitization Mol. Pharmacol., January 1, 2003; 63(1): 9 - 18. [Full Text] [PDF]
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 L. M. Luttrell and R. J. Lefkowitz The role of {beta}-arrestins in the termination and transduction of G-protein-coupled receptor signals J. Cell Sci., January 2, 2002; 115(3): 455 - 465. [Abstract] [Full Text] [PDF]
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 L. E. Vinge, E. Oie, Y. Andersson, H. K. Grogaard, G. O. Andersen, and H. Attramadal Myocardial distribution and regulation of GRK and beta -arrestin isoforms in congestive heart failure in rats Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2490 - H2499. [Abstract] [Full Text] [PDF]
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 T. Opthof Function and structure of the mouse sinus node: nothing you can see that isn't shown Cardiovasc Res, October 1, 2001; 52(1): 1 - 4. [Full Text] [PDF]
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 K. S. Kirkwood, N. W. Bunnett, J. Maa, I. Castagliolo, B. Liu, N. Gerard, J. Zacks, C. Pothoulakis, and E. F. Grady Deletion of neutral endopeptidase exacerbates intestinal inflammation induced by Clostridium difficile toxin A Am J Physiol Gastrointest Liver Physiol, August 1, 2001; 281(2): G544 - G551. [Abstract] [Full Text] [PDF]
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X.-J. Du Sympathoadrenergic mechanisms in functional regulation and development of cardiac hypertrophy and failure: findings from genetically engineered mice Cardiovasc Res, June 1, 2001; 50(3): 443 - 453. [Full Text] [PDF]
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T. A. Kohout, F.-T. Lin, S. J. Perry, D. A. Conner, and R. J. Lefkowitz beta -Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking PNAS, February 1, 2001; (2001) 41608198. [Abstract] [Full Text]
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G. Roman, J. He, and R. L. Davis kurtz, a Novel Nonvisual Arrestin, Is an Essential Neural Gene in Drosophila Genetics, July 1, 2000; 155(3): 1281 - 1295. [Abstract] [Full Text]
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F Santini, R. Penn, A. Gagnon, J. Benovic, and J. Keen Selective recruitment of arrestin-3 to clathrin coated pits upon stimulation of G protein-coupled receptors J. Cell Sci., January 7, 2000; 113(13): 2463 - 2470. [Abstract] [PDF]
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L. M. Bohn, R. J. Lefkowitz, R. R. Gainetdinov, K. Peppel, M. G. Caron, and F. Lin Enhanced Morphine Analgesia in Mice Lacking -Arrestin 2 Science, December 24, 1999; 286(5449): 2495 - 2498. [Abstract] [Full Text]
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 D. A. Kass, J. M. Hare, and D. Georgakopoulos Murine Cardiac Function : A Cautionary Tail Circ. Res., March 9, 1998; 82(4): 519 - 522. [Full Text] [PDF]
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T. A. Kohout, F.-T. Lin, S. J. Perry, D. A. Conner, and R. J. Lefkowitz beta -Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking PNAS, February 13, 2001; 98(4): 1601 - 1606. [Abstract] [Full Text] [PDF]
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