RGS2 is a feedback inhibitor of melatonin production in the pineal gland
Masahiro Matsuo, Steven L. Coon, David C. Klein⇑
The Section on Neuroendocrinology, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, MD 20892, United States
a r t i c l e i n f o
Received 22 January 2013
Revised 6 March 2013
Accepted 9 March 2013
Available online 21 March 2013
Edited by Ivan Sadowski
Regulator of G-protein signaling
a b s t r a c t
The 24-h rhythmic production of melatonin by the pineal gland is essential for coordinating circa-
dian physiology. Melatonin production increases at night in response to the release of norepineph-
rine from sympathetic nerve processes which innervate the pineal gland. This signal is transduced
through G-protein-coupled adrenergic receptors. Here, we found that the abundance of regulator
of G-protein signaling 2 (RGS2) increases at night, that expression is increased by norepinephrine
and that this protein has a negative feedback effect on melatonin production. These data are consis-
tent with the conclusion that RGS2 functions on a daily basis to negatively modulate melatonin
Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.
Daily rhythms characterize essentially all physiological func-
tions in animals . Disruption of normal 24-h rhythms in man
can cause sleep disorders and a wide range of metabolic and psy-
chiatric diseases [2,3]. An essential element in the circadian system
is melatonin, which is produced by the pineal gland and acts to
optimize circadian biology. The 24-h pattern in melatonin produc-
tion and release is controlled by the suprachiasmatic nucleus
(SCN), the central circadian clock in mammals . Time-of-day
information from SCN is transmitted to the pineal gland by a neu-
ral circuit which includes central and peripheral neural structures,
terminating in sympathetic fibers.
At night, neural signals from the SCN elicit norepinephrine re-
lease from these fibers into the pineal perivascular space; norepi-
nephrine acts through G-protein-coupled adrenergic receptors to
increase cAMP. This increases melatonin production by increasing
the activityofthe penultimateenzymeinmelatonin synthesis,aryl-
alkylamine N-acetyltransferase (Aanat), which acetylates serotonin
to produce N-acetylserotonin, the melatonin precursor. In rodents,
the increase in Aanat activity reflects in part cAMP-dependent
induction of Aanat transcription, in addition to phosphorylation .
Here we have focused on a critical element of the regulation of
melatonin production, signaling through G-proteins. G-Protein
signaling is activated by binding of GTP; hydrolysis of bound GTP
by intrinsic GTPase activity of the Ga subunit inactivates G-protein
signaling. This hydrolysis is accelerated by GTPase activating pro-
teins (GAPs), and through this mechanism, GAPs accelerate G-pro-
tein deactivation, thereby downregulates the signaling. The
regulator of G-protein signaling (RGS) family of proteins act as
GAPs and accelerate the otherwise slow intrinsic GTPase activity.
Transcription of some RGS family members is dynamically regu-
lated , and RGS2 proteins provide feedback regulation of G-pro-
tein signaling [6,7]. Here we describe the expression of RGS family
members in the rat pineal gland, and report that one negatively
regulates melatonin production.
2. Materials and methods
2.1. Animals and tissue collection
Pineal glands were prepared from Sprague Dawley rats (female,
180–250 g; Taconic Farms Inc., Germantown, NY), that had been
entrained to a 14:10 light:dark (L:D) cycle for at least one week.
Six pineal glands were pooled and used for RGS family member
expression screening; the day pool was obtained at Zeitgeber time
(ZT) 7 and the night pool at ZT19. Euthanasia at ZT19 was done un-
der a dim red light. Animal use and care protocols were approved
by local ethical review and were in accordance with National Insti-
tutes of Health guidelines.
0014-5793/$36.00 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.
⇑Corresponding author. Address: National Institutes of Health, Bldg. 49, Rm.
6A82, Bethesda, MD 20892, United States. Fax: +1 301 480 3526.
E-mail address: email@example.com (D.C. Klein).
FEBS Letters 587 (2013) 1392–1398
journal homepage: www.FEBSLetters.org
2.2. Western blotting
Protein was extracted from pineal glands for quantification of
daily or induced changes in RGS2 levels; and, from pineal cells to
quantify levels of virus-directed induction of RGS2. Protein extrac-
tion was done in radio immunoprecipitation assay buffer (50 mM
Tris pH 8.0, 150 mM NaCl, 1% Nonidet P-40, 0.5% sodium deoxycho-
late, 0.1% SDS). The lysate was centrifuged (15,000?g, 30 min, 4 ?C);
protein concentration of the supernatant was determined by the
(10 lg/lane) were resolved using 12% bis-tris SDS–polyacrylamide
gel electrophoresis in 3-(N-morpholino) propanesulfonic acid
(MOPS) buffer, and electroblotted onto Immobilon-P (Millipore,
Billerica,MA, USA) membranein NuPAGE transfer buffer.The mem-
branes were incubated for 1 h in Odyssey Blocking buffer (Li-Cor,
Lincoln, NE, USA) before overnight incubation with a polyclonal
chicken anti-full-length RGS2 (GW22245F, Sigma Aldrich, St. Louis,
MO, USA; 1:800 dilution) and monoclonal mouse anti-b-actin
(A5441,SigmaAldrich;1:5000 dilution)in Tris-buffered saline with
0.1% Tween20. After washing (Tris-buffered saline with 0.1%
Tween20, 5 min, 3 times), membranes were incubated (Tris-buf-
fered saline, 5% non-fat milk, 0.1% Tween20 and 0.02% SDS, 1 h,
room temperature) with two secondary antisera: anti-mouse IgG
(IRDye 800CW, #827-08364, Li-Cor) and anti-chicken IgG (IRDye
680LT, #926-68028, Li-Cor). Blots were visualized and band density
Imaging System (Li-Cor); RGS2 and b-actin immunopositive bands
were of the predicted size. The RGS2 signal was normalized to b-ac-
used to determine mean intensity.
2.3. Pineal cell culture
Pineal cells were prepared as described previously ; animals
were euthanized between ZT4 and ZT7. Approximately 100,000
cells were added to each well of a poly-D-lysine coated 96-well
plate (Corning, Tewksbury, MA, USA). Pineal cells were cultured
for 48 h, and then incubated in serum-free medium for 24 h prior
to and during drug treatments.
2.4. Virus infection
A replication-defective adenovirus encoding RGS2 was provided
by Peter Chidiac (University of Western Ontario, Canada) ;
b-galactosidase-encoding adenovirus (Ad-CMV-beta-gal, Vector
BioLabs, Philadelphia, PA, USA) was used as a control. After 24 h
of incubation in complete media, pineal cells were infected by
addition of adenovirus (24 h). The virus was used at a multiplicity
of infection (MOI) of 40 virus particles per cell, unless otherwise
stated. Subsequently, cells were maintained in serum-free medium
for 24 h prior to drug treatment.
2.5. mRNA quantification by qPCR
RNA from the pineal gland or pineal cells was extracted and
treated with DNase using RNeasy Micro Kit (Qiagen Inc., Valencia,
CA, USA) according to the manufacturer’s instructions. RNA quan-
tity and quality was checked by UV absorbance using a NanoDrop
1000 (Thermo Scientific, Wilmington DE, USA). cDNA was synthe-
sized from 1 lg total RNA by SuperScript III reverse transcriptase
(Life Technologies, Gland island, NY, USA) using random hexamers
at 50 ?C for 50 min. qRT-PCR was done using SYBR Green qPCR
Mastermix (Qiagen) in a LightCycler 480 (Roche, Indianapolis, IN,
USA) as described elsewhere . Molecule specific primer sets
that span at least one intron were designed by Primer-Blast
software, as listed in Supplementary Table 1. The PCR cycling
was: 95 ?C for 10 min and then 45 cycles for 95 ?C for 30 s, 60 ?C
for 30 s and 72 ?C for 30 s. Product specificity was initially con-
firmed by agarose gel electrophoresis and sequencing, and melting
curve analysis during every qRT-PCR thereafter. For each molecule,
10-fold serial dilutions of each internal standard (10 fM to 1 nM)
were used to generate a standard curve. mRNA values were nor-
malized to the abundance of Gapdh, and results are shown based
on three independent experiments.
2.6. Melatonin and N-acetylserotonin determination
A published LC/MS/MS method was used .
2.7. cAMP assay
cAMP in culture media was detected by the cAMP-Glo Assay
(Promega, Madison,WI, USA)
2.8. Data presentation and statistical analysis
All data are presented as the mean of three independent exper-
imental results ± standard error of the mean. Statistical analyses
were performed with Prism 5 for Windows (GraphPad software,
La Jolla, CA, USA). Statistical tests used are given in the text or in
the figure legends.
3.1. Transcript levels of RGS family members in the pineal gland
Expression levels of 17 RGS family members were examined by
qRT-PCR of RNA extracted from pineal glands obtained during the
day and night. Data are grouped according to subfamily member-
ship  (Fig. 1A). Except for the D/R12 family, expression of at
least one member of all subfamilies was detected. In the C/R7 sub-
family, Rgs7 was the only highly expressed member; expression
did not exhibit a day/night difference. In the A/RZ subfamily,
Rgs20 was highly expressed, with highest levels occurring at ZT7.
Three members of the B/R4 subfamily, Rgs2, Rgs4 and Rgs5 were
highly expressed, and expression of the first two exhibited a
night/day difference. The expression pattern of Rgs2 was notable
because it exhibited a ?20-fold increase at night (ZT7 vs ZT19;
P < 0.05, two-tailed t-test, n = 3 each), consistent with the day/
night difference reported based on microarray analysis .
3.2. The Rgs2 transcript and RGS2 protein exhibit similar 24-h profiles
The abundance of the Rgs2 mRNA was determined at 6 time
points throughout a 24-h period (Fig. 1B). The peak in Rgs2 expres-
sion occurred at ZT19. Expression was no more than20% of the peak
value at other times. The Rgs2 expression pattern generally resem-
bles that of Aanat and of a group of transcripts known to be con-
trolled by the SCN and to peak at night (Dio2, Fosl2, Pde4b, Pde10a,
Crem, Dusp1 ). Western blot analysis indicated that RGS2 pro-
tein exhibited similar dynamics (Fig. 1C, Supplementary Fig. 1).
3.3. Norepinephrine regulates Rgs2 transcript and protein abundance
To determine if the night time increase in Rgs2 expression could
be reproduced in vitro by norepinephrine treatment, isolated pineal
cells were treated with 1 lM norepinephrine. Rgs2 mRNA increased
immediately following norepinephrine application; the response
peaked within 2 h and decreased gradually thereafter to ?30% of
peak value by 6 h (Fig. 2A). Also, RGS protein was found to increase
M. Matsuo et al./FEBS Letters 587 (2013) 1392–1398
within2 h (Fig. 2B). However,the subsequent decreasein RGS2 pro-
tein was delayed about 2 h relative to that of Rgs2 mRNA.
3.4. cAMP controls Rgs2 transcript abundance
This rapid increase of Rgs2 mRNA is consistent with reports of a
similar response after carbacohol or geldanamycin treatment in
cultured cell lines, or after seizure in brain tissues [7,13,14]. It
has also been shown that an upstream cAMP-response element
controls Rgs2 expression regulation . In the pineal gland, nor-
epinephrine acts through cAMP to increase expression of many
genes, which in some cases appears to involve a cAMP-responsive
element (Aanat, Dio2, Fosl2, Crem, Dusp1). To examine if cAMP
might regulate Rgs2 expression in the pineal gland, we tested the
Fig. 1. Transcript levels of RGS family members in pineal glands obtained during the day or night. (A) Transcript levels of 17 RGS members in pineal gland either at day
(Zeitgeber time; ZT7, white box) or night (ZT19, black box) are shown. Rgs2, Rgs4 and Rgs20 exhibited significantly different expression levels between ZT7 and ZT19 (ZT7 vs
ZT19 of Rgs2: 1.3 ± 0.12 vs 28.9 ± 6.28; Rgs4: 11.4 ± 1.32 vs 4.7 ± 0.23; Rgs20: 26.9 ± 3.27 vs 13.4 ± 1.28, P < 0.05, two-tailed t-test, n = 3 each). Note Rgs2 was the only molecule
that had higher expression at ZT19. (B and C) Levels of Rgs2 mRNA or RGS2 protein expression are shown relative to their peak at ZT19. Gray shading indicates time when
lights were off (night time), and the expression value at ZT7 is plotted twice for presentation. For further details see Section 2.
Fig. 2. Increase of Rgs2 transcripts and RGS2 protein following treatment with norepinephrine or a cAMP analog. (A) Rgs2 transcription was induced by 1 lM norepinephrine
application, and reached its peak 2 h after stimulation. Significant induction of Rgs2 was found 1 to 4 h after stimulation (P < 0.05, one-way ANOVA vs expression level at 0 h,
n = 3 each). (B) RGS2 protein increased within 2 h by treatment with 1 lM norepinephrine (P < 0.05, one-way ANOVA vs expression level at 0 h, n = 3 each). Inset shows a
representative Western blot result of RGS2 protein expression following norepinephrine stimulation. (C) Application of the cAMP analog, dibutyryl–cAMP, induced
transcription of Rgs2 (Control vs DBcAMP, 4.3 ± 0.55% vs 100.0 ± 9.41%; P < 0.05, two-tailed t-test, n = 3 each). For further details see Section 2.
M. Matsuo et al./FEBS Letters 587 (2013) 1392–1398
effect of 1 mM dibutyryl-cAMP (DB-cAMP), a soluble cAMP analog
and found that a 6-h treatment increased Rgs2 transcript abun-
dance by >20-fold (Fig. 2C). This supports the conclusion that nor-
epinephrine acts through cAMP to control the abundance of the
Rgs2 transcript in pineal cells.
3.5. RGS2 inhibits adrenergic stimulation of N-acetylserotonin and
Based on the findings that norepinephrine elevates RGS2 pro-
tein in the pineal gland and that RGS2 protein is known to inhibit
G-protein signaling, we hypothesized that overexpression of RGS2
would inhibit G-protein signaling in this tissue. To examine this,
RGS2 protein was overexpressed by use of an adenovirus vector
RGS2 overexpression suppressed the norepinephrine-depen-
dent increase of melatonin production, as reflected in an increase
in medium melatonin (Fig. 3B). This finding was extended by using
a range of concentrations of norepinephrine, which revealed that
RGS2 reduced by 64% the maximal level of medium melatonin in
the presence of norepinephrine (Fig. 4A, Control vs RGS2;
76.1 ± 4.47 vs 27.3 ± 0.17 pmol, P < 0.05, one-way ANOVA at
100 nM norepinephrine, n = 3 each). In addition, it was found that
RGS2 overexpression decreased levels of the melatonin precursor,
N-acetylserotonin by approximately 50% (Fig. 4C). This suggested
to us that RGS2 acts by decreasing the acetylation of serotonin
Norepinephrine is a mixed a- and b-adrenergic agonist and elic-
its maximal stimulation of the pineal gland in a dual receptor
mechanism in which b-adrenergic stimulation of adenylyl cyclase
is essential; this is enhanced by a-adrenergic elevation of intracel-
lular Ca2+and translocation of protein kinase C . In studies in
which RGS2 was overexpressed, we found that this suppressed
melatonin production in cells treated with isoproterenol, a
selective b-adrenergic agonist by 47% (Fig. 4B, Control vs RGS2;
63.8 ± 1.77 vs 34.0 ± 1.25 pmol, P < 0.05 one-way ANOVA at 1 nM
isoproterenol, n = 3 each). Similar effects were seen with medium
N-acetylserotonin (Fig. 4D). These findings indicate that RGS2
inhibits melatonin production by inhibiting b-adrenergic signaling.
3.6. RGS2 suppresses cAMP production
To determine if cAMP production was reduced by RGS2, we
measured medium cAMP concentrations after 15 min of norepi-
nephrine stimulation of pineal cells in which GRS was overexpres-
sed (Fig. 4E). This revealed that RGS2 decreased the cAMP amount
in media when cells were treated with 10 lM norepinephrine
(Fig. 4E, Control vs RGS2; 136.5 ± 7.04 vs 87.7 ± 4.75 nM, P < 0.05
one-way ANOVA at 10 lM norepinephrine, n = 3 each). This pro-
vides evidence that cAMP production by pineal cells is reduced
3.7. RGS2 suppresses the adrenergic induction of Aanat and other
adrenergic cAMP-inducible genes
Based on the findings that RGS2 inhibited N-acetylserotonin
and cAMP production, it is likely that inhibition of RGS2 reflects
in part a decrease in AANAT activity. This might occur as a result
of a decrease in Aanat transcription, which in turn would result
in a decrease in protein and enzyme activity. Analysis of Aanat
mRNA indicated that RGS2 suppressed by approximately 50% the
norepinephrine stimulation of Aanat mRNA (Fig. 5B, Control vs
RGS2; P < 0.05, one-way ANOVA, n = 3 each). In the same experi-
ment, we found that the expression levels of Tph1, the first enzyme
in the tryptophan to melatonin pathway did not change as a func-
tion of RGS2 infection in control or norepinephrine-treated cells,
providing indication that the effect of viral infection was selective.
It was also found that RGS2 regulates other transcripts regu-
lated by norepinephrine–cAMP signaling , including Dio2 and
Fosl2 (Fig. 5C and D). Expression of both was inhibited by RGS2
overexpression, thereby providing evidence of broad effects of
RGS2 on adrenergic stimulation of gene expression in the pineal
The results presented in this report provide the first evidence
that pineal signal transduction is regulated at the G-protein level
through a member of the RGS family proteins. The finding that nor-
epinephrine controls the abundance of RGS2 supports the conclu-
sion that a negative feedback loop exists in which stimulation of
pineal cells by norepinephrine elevates RGS2 which in turn atten-
uates adrenergic stimulation, as outlined in Fig. 6. Analyses of mel-
melatonin production at the first step in the serotonin ? N-ace-
tylserotonin ? melatonin pathway, serotonin acetylation by
The mechanism through which RGS2 inhibits serotonin acetyla-
tion appears to involve inhibition of Aanat transcription, based on
our results. Moreover, in view of the evidence that cAMP mediates
norepinephrine regulation of RGS2 and that norepinephrine ele-
vates pineal cAMP, we believe that RGS2 inhibits Aanat induction
through a suppressive effect on cAMP production, as in other tis-
sues . This conclusion is supported by the finding that RGS2
also inhibits induction of other cAMP-regulated genes in the pineal
gland, including Dio2 and Fosl2. Accordingly, it is not only reason-
able to suspect that RGS2 is acting on melatonin synthesis by sup-
pressing cAMP-dependent induction of Aanat, but that suppression
of cAMP might also result in a decrease in cAMP-dependent
indicate that RGS2impacts
Fig. 3. RGS2 inhibits melatonin production in a dose-dependent manner. (A)
Western blot of cell lysates infected with serial titers of RGS2-coding adenovirus;
1.1 to 90 virus particles per cell (MOI). The increase in pineal RGS2 protein was
titer-dependent. (B) Virus titer-dependent decrease of melatonin production in
pineal cells. Although no significant decrease of melatonin was found up to 10 virus
particles per cell, a significant and titer-dependent decrease by RGS2 was found at
30 and 90 virus particles per cell (P < 0.05, one-way ANOVA, Control vs RGS2
infected cells at same virus concentration, n = 3 each). For further details see
M. Matsuo et al./FEBS Letters 587 (2013) 1392–1398
phosphorylation of AANAT, which would in turn decrease enzyme
activity because posttranslational phosphorylation promotes AA-
NAT stability and activity .
The evidence that RGS2 suppresses induction of two other
adrenergic–cAMP regulated genes in the pineal gland points to
the likelihood that RGS2 broadly impacts pineal biology by inhib-
iting the adrenergic–cAMP regulation of hundreds of genes in this
tissue , thereby playing a broad governing role.
As such, RGS2 joins a growing group of proteins that contribute
to negative feedback of adrenergic stimulation of pineal function.
This group includes PDE4B, which like RGS2 is (1) induced by nor-
epinephrine acting through a cAMP mechanism and (2) suppresses
norepinephrine–cAMP signaling . In the case of PDE4B and
perhaps PDE10A, the mechanism involves increased cAMP degra-
dation. In addition, another mechanism that represses pineal
cAMP-directed transcription involves Snf1-lk/SIK induction .
Early work on signal transduction in the pineal gland clearly
established that mechanisms exist to control daily change of pineal
sensitivity to adrenergic signals . It would appear that the phe-
nomenon of subsensitivity can now be explained on a molecular
level in part by the daily induction of Rgs2, Pde4b, Pde10a, and
Snf1-lk/SIK, acting through several negative feedback mechanisms
focusing on cAMP signaling to govern the magnitude of the re-
sponse of the pinealocyte to norepinephrine.
We found that two other highly expressed RGS family members,
Rgs4 and Rgs20, exhibited ?2-fold higher expression in the day
Fig. 4. RGS2 inhibits norepinephrine- and isoproterenol-dependent elevation of N-acetylserotonin, melatonin and cAMP in pinealocyte culture media. Pineal cells were
stimulated by a range of concentrations of norepinephrine (A and C) or isoproterenol (B and D). Significant inhibition of melatonin and N-acetylserotonin production by RGS2
occurred at concentrations of 10?9–10?6and 10?8–10?6M norepinephrine, respectively (A and C, P < 0.05, one-way ANOVA, Control vs RGS2-infected cells at the same
concentration of norepinephrine, n = 3 each). Significant inhibition of both melatonin and N-acetylserotonin production by RGS2 was found at the concentrations of 10?9–
10?8M isoproterenol (B and D, P < 0.05, one-way ANOVA, Control vs RGS2-infected cells at the same concentration of isoproterenol, n = 3 each). (E) Norepinephrine
stimulation of cAMP content of media was decreased in cultures of cells in which RGS2 was overexpressed (P < 0.05, one-way AVNOVA, Control vs RGS2-infected cells at
10?5lM norepinephrine, n = 3 each). For further details see Section 2.
M. Matsuo et al./FEBS Letters 587 (2013) 1392–1398
time. The antiphase relationship to the dynamics of Rgs2 raises the
possibility that these molecules might also modulate G-protein
signaling, and modify those of RGS2. Although Rgs2 and Rgs4 be-
long to the same B/R4 subfamily, opposite transcriptional
regulation has been reported . Rgs20 is a member of A/RZ sub-
family and mainly targets Gaz ; therefore, interference in the
action of Rgs2 is unlikely because it primarily targets Gas and
Besides the regulation of G-proteins, RGS2 acts through other
mechanisms to regulate signaling pathways. Direct interactions
with adenylyl cyclase III and V have been reported [22,23]; how-
ever, neither is highly expressed in the pineal gland (unpublished
data). Also, emerging data has described RGS2 regulation of tran-
sient receptor potential (TRP) ion channels, specifically TRPV6
; although it is expressed at low levels in the pineal gland
(unpublished data), other members of this family which are highly
expressed might be RGS2 targets.
In conclusion, the results of our studies indicate that RGS2 is ex-
pressed on a 24-h schedule in the pineal gland by a norepineph-
rine–cAMP mechanism; and, that this constitutes a negative
feedback mechanism that suppresses effects of norepinephrine,
including melatonin production and induction of several genes.
This suggests that RGS2 acts broadly to govern G-protein signaling
in the pineal gland, and therefore RGS2 might have a suppressive
role in the daily pattern of melatonin production. Moreover, a sim-
ilar 24-h cAMP-RGS2 feedback mechanism may function in other
tissues to influence daily changes in cAMP-driven gene expression,
and malfunction of this mechanism can lead to disease.
This work was supported by the Intramural Research Program
of the NICHD. We express appreciation to Peter Chidiac for provid-
ing the RGS2 adenovirus and valuable scientific input.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.febslet.2013.03.
Fig. 5. RGS2 inhibits the norepinephrine-dependent increase of the abundance of Aanat, Dio2 and Fosl2 transcripts. The effect of RGS2 overexpression on the abundance of
several transcripts was determined following by a 2-h application of 1 lM norepinephrine. Norepinephrine did not increase the abundance of Tph1 mRNA (A). However, a
greater than 5-fold increase was observed for Aanat (B), Dio2 (C) and Fosl2 (D). Increased transcript levels in RGS2-infected cells was decreased to 47.7% for Aanat, to 47.1% for
Dio2, and to 66.0% for Fosl2 (P < 0.05, one-way ANOVA, n = 3 each) compared to norepinephrine-stimulated control cells. For further details see Section 2.
Fig. 6. Schematic presentation of negative regulation of melatonin synthesis by
RGS2. RGS2 is induced by the daily release of norepinephrine which binds to a1b-
and b1-adrenergic receptors and activates adenylyl cyclase. The resulting increase
in cAMP leads to the transcription of several genes including Rgs2. Translated RGS2
protein inhibitsG-protein signaling
M. Matsuo et al./FEBS Letters 587 (2013) 1392–1398
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