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J Biol Chem, Vol. 274, Issue 42, 29689-29693, October 15, 1999
From the Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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RGS2, a member of the Regulators of
G-protein Signaling family, modulates the
activity of G-proteins coupled to the phosphoinositide signal
transduction system, but little is known about what regulates RGS2. In
human neuroblastoma SH-SY5Y cells stimulation of muscarinic receptors
by carbachol activates phosphoinositide signaling and also caused a
rapid, large, and long lasting increase in RGS2 mRNA levels. Direct
activation of protein kinase C also rapidly increased RGS2 mRNA
levels. Inhibition of protein kinase C with Ro31-8220, GF109203x, or
Go6976 or down-regulation of protein kinase C inhibited increases in
RGS2 mRNA levels induced by carbachol or by the activation of
protein kinase C. Blockade of calcium signaling did not alter
carbachol-induced increases in RGS2 mRNA levels. Neither activation
of epidermal growth factor receptors nor stimulation of cyclic AMP
production with forskolin increased RGS2 mRNA levels. Pretreatment
with actinomycin D blocked increases in RGS2 mRNA levels but caused
a surprisingly small, although statistically significant, partial
blockade of protein kinase C-mediated feedback inhibition of
carbachol-induced phosphoinositide hydrolysis. Thus, RGS2 mRNA
levels are increased by activation of muscarinic receptors coupled to
the phosphoinositide signal transduction system through a protein
kinase C-dependent mechanism. This action may contribute to
negative feedback control of this signaling cascade, but because the
small contribution to negative feedback contrasts with the large and
prolonged elevations in RGS2 mRNA levels, we speculate that its
primary role may be in modulating other signaling components.
The recent discovery of a family of Regulators of
G-protein Signaling
(RGS)1 proteins has provided
new insights into mechanisms regulating the signaling cascades
initiated by activation of G-protein-coupled receptors (1-3). RGS
proteins contribute to the control and cross-talk of signaling cascades
by interacting with activated G-protein RGS2 is of particular interest to investigators studying the
phosphoinositide signal transduction system in the brain (8). RGS2 has
been linked with regulation of Gq/11, the G-proteins mediating
receptor-coupled phosphoinositide hydrolysis, where it functions as a
potent inhibitor of Gq/11-mediated activation of phospholipase C (5, 7,
9). Furthermore, RGS2 is rapidly regulated by neuronal activity, as the
mRNA level for RGS2 but not seven other RGS subtypes was rapidly
and transiently increased by treatments that increase neuronal
activity, such as electroshock, in a manner reminiscent of immediate
early genes, such as c-fos (9). RGS2 mRNA levels also
have been reported to be increased in selective brain regions after
treatment of rats with haloperidol (9), amphetamine, cocaine,
methamphetamine, or raclopride (9-11). Initial studies of RGS2
mRNA levels in cultured cells have identified several regulatory
agents. Concanavalin A stimulated the expression of RGS2 in blood
mononuclear cells (12, 13), elevation of cyclic AMP increased RGS2
mRNA levels in PC12 cells and T cells (14, 15), and the calcium
ionophore ionomycin increased RGS2 mRNA in blood mononuclear cells
(13) but not in PC12 cells (14). Overall, these studies indicate that
RGS2 modulates the activity of the phosphoinositide signal transduction
system and is itself subject to rapid regulation through modulation of
its expression.
Muscarinic receptor-coupled activation of the phosphoinositide signal
transduction system has been studied extensively in human neuroblastoma
SH-SY5Y, which endogenously express muscarinic M3 receptors linked to
phosphoinositide signaling (16-18). Therefore, these cells were used
in the present study to determine if RGS2 mRNA levels are subject
to modulation by activation of the phosphoinositide signaling system.
The results show that in SH-SY5Y cells muscarinic receptor activation
leads to rapid, large, and long lasting increases in RGS2 mRNA
levels through a protein kinase C-dependent mechanism, and
inhibition of transcription when protein kinase C is stimulated reduces
feedback inhibition of phosphoinositide hydrolysis.
Cell Culture--
Human neuroblastoma SH-SY5Y cells were grown
in RPMI medium (Cellgro, Herndon, VA) supplemented with 10% horse
serum (Life Technologies, Inc.), 5% fetal clone II (Hyclone, Logan,
UT), 2 mM L-glutamine, 100 units/ml penicillin,
and 100 µg/ml streptomycin. Cells were maintained in humidified
37 °C chambers with 5% CO2. Cells were plated at a
density of approximately 105 cells/100-mm dish and were
treated with experimental agents approximately 48 h later. Agents
used include carbachol, phorbol 12-myristate 13-acetate (PMA), nickel
chloride, epidermal growth factor, and actinomycin D from Sigma;
Ro31-8220, GF109203x, Go6976, and forskolin from Alexis Biochemicals
(San Diego, CA); KN62 from Seikagaku America (Rockville, MD); and
1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) from Calbiochem.
Northern Blots--
RGS2 cDNA was generously provided by Dr.
D. R. Forsdyke (Queen's University, Kingston, Ontario, Canada).
Total mRNA was extracted using Trizol reagent (Life Technologies,
Inc.) according to the manufacturer's instructions. RNA (10 µg) was
separated by electrophoresis in 1.2% agarose gels containing
formaldehyde and transferred to nitrocellulose membranes. cDNA was
random prime-labeled with [32P]dCTP (Amersham Pharmacia
Biotech). Blots were hybridized with labeled probes at 42 °C for
18 h and then washed in two changes of 2× saline-sodium citrate
and 0.1% SDS at 20 °C for 20 min and once in 1× saline-sodium
citrate and 0.1% SDS at 55 °C for 10 min. Results were obtained
using a PhosphorImager (Molecular Dynamics, Sunnyvale, CA), and all
experiments were repeated 2-4 times.
Phosphoinositide Hydrolysis--
Cells were prelabeled with 7.5 µCi/ml myo[2-3H]inositol (American Radiolabeled
Chemicals, St. Louis, MO) for 48 h. Where indicated, cells were
treated with 1 µM actinomycin D to inhibit transcription or an equivalent amount of dimethyl sulfoxide (Me2SO) for
15 min and 0.2 µM PMA for a subsequent 2 h to induce
feedback inhibition of phosphoinositide hydrolysis. Cells were
harvested, resuspended in buffer (30 mM HEPES, pH 7.4, 122 mM NaCl, 3.6 mM NaHCO3, 1.2 mM KH2PO4, 1.2 mM
MgCl2, 5 mM KCl, 1.3 mM
CaCl2, 10 mM LiCl, 11 mM glucose),
and washed two times, as described previously (16). Suspended cells
were incubated for 15 or 30 min with or without 1 mM
carbachol at 37 °C, and radioactivity was measured in samples after
fractionation of lipids, inositol monophosphate, and inositol as
described previously (16). Measurements were made in triplicate for
each treatment in at least three separate experiments. Statistical significance was determined using a paired Student's t test.
RGS2 mRNA levels were measured in human neuroblastoma SH-SY5Y
cells treated with 1 mM carbachol for 15 min to 24 h.
Fig. 1A shows results from a
representative time-course experiment demonstrating that RGS2 mRNA
levels rapidly increased upon stimulation of muscarinic receptors with
carbachol, whereas actin mRNA levels remained unchanged. Maximal
levels of RGS2 mRNA were attained between 90 and 120 min of
exposure to carbachol, and pretreatment with the muscarinic receptor
antagonist atropine (1 µM) completely blocked
carbachol-induced increases in RGS2 mRNA. Thus, stimulation of
endogenous muscarinic receptors that are coupled to the
phosphoinositide signal transduction system causes a rapid, large, and
prolonged increase in RGS2 mRNA levels.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-subunits to facilitate
their intrinsic inactivating GTPase reaction. By this, and likely other
mechanisms (4-7), RGS proteins participate in limiting the activities
of G-protein -subunits and regulating the activities of signaling
cascades. How RGS proteins themselves are regulated has begun to be
examined in recent investigations, which have generated evidence that
one important site of control is at the level of gene expression
(2).
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
View larger version (20K):
[in a new window]
Fig. 1.
Carbachol and protein kinase C activation
increased RGS2 mRNA levels. A, RGS2 and actin
mRNA levels were measured in SH-SY5Y cells treated with 1 mM carbachol (Carb) for 15 min to 24 h.
Pretreatment with 1 µM atropine (AT) for 10 min blocked the increase in RGS2 mRNA caused by treatment with 1 mM carbachol for 60 min. B, RGS2 and actin
mRNA levels were measured in SH-SY5Y cells treated with 0.2 µM PMA for 15-180 min.
Phosphoinositide signaling activates protein kinase C, which is known
to cause feedback inhibition of phosphoinositide signaling activity.
Therefore protein kinase C was examined as a potential regulator of
RGS2 expression. Activation of protein kinase C with 0.2 µM PMA caused a time-dependent increase in
RGS2, but not actin, mRNA levels (Fig. 1B). If protein
kinase C participates in muscarinic receptor-induced increases in RGS2
mRNA levels, then inhibitors of protein kinase C should cause
similar reductions in the increases in RGS2 mRNA levels induced by
the activation of protein kinase C and stimulation of muscarinic
receptors. To test this, several protein kinase C inhibitors were used.
Two bisindolylmaleimide derivatives, GF109203x and Ro31-8220, inhibited
increases in RGS2 mRNA levels induced by treatment with carbachol
or PMA with 10 µM GF109203x causing inhibitions of
50-60% and 10 µM Ro31-8220 causing almost 90%
inhibition with each stimulant (Fig. 2).
Increases induced by PMA and carbachol also were inhibited similarly by an inhibitor of classical protein kinase C subtypes, 10 µM Go6976 (68 ± 2 and 58 ± 11% inhibition,
respectively), and by down-regulation of protein kinase C attained by a
24-h pretreatment with 1 µM PMA (48 ± 6 and 47 ± 7% inhibition, respectively). In contrast, carbachol-stimulated
RGS2 mRNA levels were unaffected by several agents affecting
calcium signaling (Fig. 3A)
including 20 µM
1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (an intracellular calcium chelator), 2 mM nickel chloride (an inhibitor of the plateau phase of
carbachol-stimulated increases in intracellular calcium), and 30 µM KN62 (an inhibitor of
calcium/calmodulin-dependent kinase II). This lack of
effects contrasts with previous studies using each of these agents
affecting calcium signaling that demonstrated effects on other
signaling systems activated by carbachol in SH-SY5Y cells (19).
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In contrast to stimulation of muscarinic receptors and activation of protein kinase C, two other signaling agents failed to cause increases in RGS2 mRNA levels. Treatment with epidermal growth factor, which activates signaling through increased protein tyrosine phosphorylation in SH-SY5Y cells (20), caused little change in RGS2 mRNA levels (Fig. 3B). Forskolin, which causes increases in cyclic AMP and has been reported to increase RGS2 mRNA levels in PC12 cells (14), did not increase but actually decreased RGS2 mRNA levels (Fig. 3C).
To test if RGS2 might contribute to the well known feedback inhibition
of phosphoinositide signaling induced by activation of protein kinase
C, actinomycin D was used to inhibit transcription. Pretreatment with 1 µM actinomycin D completely blocked increases in RGS2
mRNA (Fig. 4A). In
nonpretreated SH-SY5Y cells, carbachol induced a rapid and robust
activation of phosphoinositide hydrolysis, attaining at 15 min of
incubation an 8-fold stimulation over the basal rate of
phosphoinositide hydrolysis (Fig. 4B). Activation of protein
kinase C using a 2-h pretreatment with 0.2 µM PMA caused an approximately 70% inhibition of the subsequent carbachol-stimulated phosphoinositide hydrolysis (Fig. 4C). Inhibition of
transcription with actinomycin D during the pretreatment with PMA
significantly reduced the inhibitory effect on carbachol-stimulated
phosphoinositide hydrolysis, with responses attained that were 139 and
124% of those obtained in PMA-treated cells without transcription
blockade. Treatment with actinomycin D without PMA treatment did not
alter carbachol-stimulated phosphoinositide hydrolysis (data not
shown). These results indicate that a portion of the PMA-induced
inhibition of phosphoinositide signaling requires activation of gene
expression, a finding consistent with the hypothesis that the
expression of RGS2 following stimulation of protein kinase C makes a
significant contribution to this feedback inhibitory action.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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This study adds to a small but growing body of research revealing the exquisite responsiveness of RGS2 mRNA levels to extracellular stimuli, as reviewed in the Introduction. The rate at which RGS2 mRNA levels increased after stimulation of muscarinic receptors is comparable to that of the classical c-fos and c-jun immediate early genes (21, 22), a similarity noted previously in a study of increases in RGS2 mRNA levels in rat brain in response to electroshock (9). However, increases in RGS2 mRNA levels in SH-SY5Y cells after muscarinic receptor stimulation were relatively long lasting, as the elevation was still evident after 24 h of stimulation with carbachol. Thus, muscarinic receptor activation results in rapid and large, but also prolonged, elevations in RGS2 mRNA levels.
Protein kinase C appears to mediate a significant portion of the muscarinic receptor-induced increase in RGS2 mRNA levels. Both stimulation of muscarinic receptors coupled to phosphoinositide signaling and activation of protein kinase C, a second messenger-linked outcome of phosphoinositide signaling, increased RGS2 mRNA levels, and these responses were inhibited equivalently by four treatments that inhibit the activity of protein kinase C. Ro31-8220 was the most effective inhibitor of the induction of RGS2 mRNA, but recent studies have discovered several actions of this agent independent of its inhibition of protein kinase C, some of which may contribute to the practically complete inhibition caused by Ro31-8220 (23-25). The other three treatments, GF109203x, Go6976, and protein kinase C down-regulation, caused 50-60% inhibitions of carbachol- or PMA-induced increases in RGS2 mRNA levels, suggesting that protein kinase C subtypes in the classical family may mediate this portion of the response. Phorbol ester-induced activation of protein kinase C previously was reported to increase the mRNA level of RGS7, but not RGS4, in primary cortical neurons after 12 h of treatment (26) but did not increase RGS2 mRNA levels in blood mononuclear cells (13). Although this is still a limited amount of information, it indicates that, not unexpectedly, there are differences in the mechanisms that regulate mRNA levels for different members of the RGS family of proteins and there are cell-specific differences in the regulation of RGS2 mRNA levels.
RGS2 regulates the activity of Gq/11, and for this effect RGS2 is 10-fold more potent than RGS4 (5); in the current study activation of phosphoinositide signaling and of protein kinase C increased RGS2 mRNA levels. These properties suggest that RGS2 may be a regulator of the activity of the phosphoinositide signal transduction system. Our findings on the PMA-induced feedback inhibitory regulation of phosphoinositide signaling are consistent with this proposal but only to a limited extent. Stimulation of protein kinase C using a 2-h pretreatment with PMA inhibited carbachol-stimulated phosphoinositide hydrolysis by 70%, a regulatory influence that has been known for many years but for which a mechanistic basis has not been delineated. Inhibition of transcription by actinomycin D both blocked increases in RGS2 mRNA levels and attenuated the inhibition of phosphoinositide hydrolysis caused by activation of protein kinase C. Taken together, all of these results are consistent with the hypothesis that activation of protein kinase C increases RGS2 expression, which attenuates the activity of the G-proteins mediating phosphoinositide signaling, although selective knockouts of RGS2 will be necessary to fully test this scheme. However, the minor portion of the protein kinase C-induced inhibition of phosphoinositide signaling that was blocked by actinomycin D treatment indicates that other mechanisms contribute the major share to this feedback inhibition. This raises the intriguing possibility that physiological increases in RGS2 may primarily serve other functions. This speculation will be better tested once antibodies are available to measure RGS2 protein levels and after the diverse actions of RGS2 are more completely identified.
In summary, stimulation of muscarinic receptors increased RGS2 mRNA
levels through a mechanism partially dependent on protein kinase C
activation, and transcription was necessary for maximal feedback
inhibition by protein kinase C of phosphoinositide signaling. It is
likely that other receptors coupled to the phosphoinositide signal
transduction system also will modulate RGS2 mRNA levels because
protein kinase C mediated a portion of this regulatory response. Thus,
stimulation of RGS2 expression may contribute to the control of
phosphoinositide signaling activity, and considering the multiple
functions of RGS proteins that are being identified, RGS2 may
constitute a rapid intracellular mediator of cross-talk among signaling systems.
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ACKNOWLEDGEMENTS |
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We thank Dr. D. R. Forsdyke for generously providing the RGS2 cDNA.
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FOOTNOTES |
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* This work was supported by National Institutes of Health Grants MH38752 and AG06569.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Psychiatry,
Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL
35294-0017. Tel.: (205) 934-7023; Fax: (205) 934-3709; E-mail:
jope@uab.edu.
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ABBREVIATIONS |
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The abbreviations used are: RGS, regulators of G-protein signaling; PMA, phorbol 12-myristate 13-acetate.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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