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Section of Gastroenterology, Boston Veterans Administration Medical Center, and Boston University School of Medicine, Boston, Massachusetts 02118
Address all correspondence and requests for reprints to: Chi-Chuan Tseng, M.D., Ph.D., Section of Gastroenterology, Boston University School of Medicine, Boston, Massachusetts 02118.
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protein in an in
vitro system, suggesting that RGS2 attenuated the
Gs-adenylate cyclase signaling pathway. These results
suggest a potential role for RGS2 in modulating GIP-mediated insulin
secretion in pancreatic islet cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several studies have been performed in the past that have attempted to define the role, if any, of GIP in the pathophysiology of noninsulin-dependent diabetes mellitus. Some (8, 9, 10) have reported normal serum GIP levels, whereas others (11, 12, 13) have detected elevated serum GIP concentrations in patients with noninsulin-dependent diabetes mellitus. Further studies examining the function of GIP have demonstrated that the insulinotropic properties of GIP in diabetic patients were greatly diminished despite their elevated serum GIP levels. Our laboratory has recently reported that GIP gene expression was enhanced in streptozotocin-induced diabetic rats, and that continuous or repetitive GIP stimulation resulted in a decrease in insulin release in the rat (14). These results are consistent with the idea that elevated serum GIP levels in diabetic patients might induce homologous desensitization of the GIP receptor (GIP-R) on the pancreatic islet cells and that this mechanism could contribute to the impaired insulin secretion seen in these patients.
Although the precise mechanism for the decline in the insulinotropic
activity of GIP in diabetic patients and animals has not been defined,
agonist-induced desensitization of G protein-coupled receptors is a
well documented phenomenon. Upon agonist stimulation, some receptors
are phosphorylated by protein kinase and result in uncoupling them from
interaction with G protein (15). Recently, an interaction of the G
protein with members of RGS proteins (regulators of G protein
signaling) has been demonstrated to mediate a desensitization mechanism
(16, 17, 18). In this process, RGS proteins act as guanosine
triphosphatase-activating protein to decrease the half-life of the
activated G subunit (19, 20). Although these proteins were first
identified in yeast (21, 22), at least 15 members of this family have
been described in mammals (16, 17, 18). In this paper, we have investigated
the potential role of RGS in the homologous desensitization of the
GIP-R on ßTC3 cells and on GIP-R complementary DNA (cDNA)-transfected
human embryonal kidney cells (L293).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell transfection
L293 and ßTC3 cells were transfected with GIP-R cDNA (0.75
µg) and one of the four RGS cDNAs (0.75 µg) borne by eukaryotic
expression vectors [RGS1 pRC/CMV (1.4 kb), RGS2 pRC/CMV (0.8 kb), RGS3
pRC/CMV (1.7 kb), or RGS4 pCR3 (0.7 kb); provided by J. H. Kehrl]
using the Lipofectamine method according to the manufacturer’s
protocol (Life Technologies, Gaithersburg, MD). Briefly,
cells were seeded in a 12-well plate (105 cells/well) and
cultured overnight in the presence of medium with 10% FBS. For
transfection, DNA was diluted into serum-free medium, and Lipofectamine
(4 µl/well) was added and incubated at room temperature for 15 min to
allow DNA-liposome complexes to form. During this 15-min period, cells
were rinsed twice with serum-free medium and then incubated with 1 ml
DNA-liposome for 5 h. After incubation, 1 ml medium supplemented
with 20% FBS was added, and the cells were incubated for an additional
48 h before analysis. In some experiments, cells were
cotransfected with pCMV-ß-galactosidase plasmid to determine
transfection efficiency. In general, transfection efficiency was
similar with different cDNAs, but was higher in L293 cells than in
ßTC3 cells. The percentage of cells staining positively for
ß-galactosidase after transfection was approximately 45% for L293
cells and 36% for ßTC3 cells.
GIP iodination
GIP was iodinated using the chloramine-T method (23). The
iodinated peptide was then added to a Waters C18 Sep-Pak
cartridge (Waters, Milford, MA) preequilibrated with 10 ml acetonitrile
(HPLC grade) and 10 ml water, both containing 0.1% trifluoroacetic
acid. The iodinated products were eluted by a 2% stepwise gradient of
acetonitrile-water (2 ml) from 30–42%. Each fraction was collected
into a tube containing 100 µl aprotinin (Miles, Kankakee, IL) and 100
µl BSA (100 mg/ml; protease-free; Sigma Chemical Co.,
St. Louis, MO). Aliquots were tested for binding to GIP antiserum, and
the fraction with the highest specific binding was lyophilized and
stored at -20 C.
Receptor binding
The binding assay was performed with the intact cells.
Forty-eight hours after transfection, cells were rinsed twice in
binding buffer (138 mM NaCl, 5.6 mM KCl, 1.2
mM MgCl2, 2.6 mM CaCl2,
10 mM HEPES, 1% BSA, and 10 mM glucose) and
then incubated with 30 µl (30,000 cpm/tube) [125I]GIP
and 300 µl binding buffer or 3 µl cold GIP (final concentration,
10-6 M). Plates were incubated on a rocker at
room temperature for 45 min. At the end of incubation, plates were
washed twice with 0.5 ml binding buffer containing 4% BSA, and cells
were detached with 0.5 ml trypsin-EDTA. The samples were counted in a
-counter, and total specific binding was determined by subtracting
nonspecific binding obtained in the presence of 10-6
M unlabeled GIP from total cell-associated radioactivity.
Nonsaturable binding was always less than 10% of the total binding.
Receptor binding data were analyzed using the RADLIG program
(Biosoft, Cambridge, UK).
Desensitization of GIP-R
GIP-R cDNA-transfected L293 cells were split 1:2, and 48 h
later, half of the cells were resuspended in MEM containing
10-7 M GIP for 10 min, whereas the other half
were cultured in MEM alone. At the end of preincubation, cells were
washed with PBS until cAMP returned to the basal level and then were
incubated with 500 µl medium and 100 µM IBMX, followed
by the appropriate concentrations of GIP. Cells were incubated for 10
min at 37 C and extracted with 500 µl cold absolute ethanol, followed
by freeze-thawing. The lysed cells were collected, and the cAMP levels
were measured by RIA (cAMP assay kit, Amersham, Arlington
Heights, IL). Desensitization was measured by treating control and
GIP-preincubated cells in parallel and then expressing the residual
ability to increase cellular cAMP levels in both cells.
Insulin secretion
For the measurement of insulin release, experiments were carried
out in Krebs-Ringer bicarbonate (KRB) buffer (pH 7.4) containing 129
mM NaCl, 5 mM NaHCO3, 4.8
mM KCl, 1.2 mM KH2PO4,
1.0 mM CaCl2, 1.2 mM
MgSO4, 10 mM HEPES, and 0.1% BSA. Glucose
concentrations were stated in the individual experiments. One day after
transfection, ßTC3 cells were incubated in the presence of
glucose-free DMEM overnight. Cells were washed with fresh glucose-free
KRB buffer twice and incubated with the same buffer for 10 min. After
removal of the incubation buffer, cells were washed with glucose-free
KRB buffer again and exposed for another 30 min to fresh KRB buffer
containing the test agents (5 mM glucose or/and GIP).
Samples of the incubation medium were collected, centrifuged at 4 C to
get rid of cell debris, and stored at -20 C until RIA was performed
(rat insulin RIA kit, Linco Research, Inc. St. Charles,
MO).
Northern blot hybridization analysis
Total RNA from ßTC3 and L293 cells was extracted using the
acid-phenol method of Chomczynski and Sacchi (24). Northern blot
hybridization analysis was performed using stringent conditions [42 C,
50% (vol/vol) formamide and 5 x sodium saline citrate (SSC);
1 x SSC = 0.15 M NaCl-0.15 M sodium
citrate, pH 7.2]. Ten micrograms of total RNA were denatured in
gel-running buffer [0.04 M
3-(N-morpholino)propanesulfonic acid, 10 mM
sodium acetate, 0.5 mM EDTA (pH 7.5), 50% formamide, and
6% formaldehyde]. The RNA was then electrophoresed on a 1.5%
agarose-6% formaldehyde gel. The integrity of the extracted RNA was
determined by visualization of 28S and 18S ribosomal RNA bands with
ethidium bromide staining. After electrophoresis at 10 V/cm, the RNA
was transferred from the gel to a Duralon-UV filter by capillary
action, as described by the manufacturer (Stratagene, La
Jolla, CA). Hybridization was then performed using the RGS2 and mouse
cyclophilin (Ambion, Inc., Austin, TX) cDNAs that were
radiolabeled with [32P]deoxy-CTP using the Klenow
fragment of DNA polymerase I and random oligonucleotides as primers
(Promega Corp., Madison, WI). The blots were prehybridized
for 2 h at 42 C in 5 x SSC, 10 x Denhardt’s solution,
50% (vol/vol) formamide, 50 mM NaPO4, 1% SDS
(BRL, Gaithersburg, MD), and 10 g/ml herring sperm DNA (Sigma Chemical
Co.). The filters were then hybridized at 42 C for 16–24 h in 5
x SSC, 1 x Denhardt’s solution, 50% formamide, 20
mM NaPO4, 0.5% SDS, and herring sperm DNA at
20 µg/ml and approximately 107 cpm
probe/100-cm2 filter. After hybridization, blots were
washed once at room temperature in 1 x SSC-1% SDS for 15 min,
once at room temperature in 0.5 x SSC-0.5% SDS for 15 min, twice
at room temperature in 0.1 x SSC-0.1% SDS for 15 min, and once
at 50 C in 0.1 x SSC-0.1% SDS for 30 min. Autoradiograms were
developed after exposure to x-ray film for 12–96 h at -70 C, using a
Cronex intensifying screen (DuPont, Wilmington, DE). The
hybridization signals were quantified by laser densitometry and
integration of the autoradiographic images.
RGS2 binding of Gs protein
Oligo-directed mutagenesis (Altered Sites In Vitro Mutagenesis
System, Promega Corp.) was used to add nine amino acids
(YPYDVPDYA) to the carboxyl-terminus of the RGS2 cDNA immediately
before the termination codon (25). These nine amino acids constitute a
hemagglutinin (HA) epitope recognized by the commercially available
antibody. Positive mutations were verified using dideoxy-DNA sequencing
(Sequenase kit, Amersham). Once verified, the mutant insert (RGS2-HA)
was subcloned into pcDNA III plasmid (Invitrogen, San
Diego, CA). RGS2-HA protein was prepared from in vitro
transcription and translation in the presence of
[35S]methionine (Amersham) using a rabbit reticulocyte
lysate system (TNT T7 Quick Coupled
Transcription/Translation System, Promega Corp.). pcDNA
III plasmid and luciferase DNAs (provided by Promega
Corp.) were used as controls.
Binding studies of [35S]Met-RGS-HA protein to
Gs were performed in PBS (pH 7.4) containing
0.1% Triton X-100 as previously described (26). Ten micrograms of
Gs (obtained from Santa Cruz
Biotechnology, Inc., Santa Cruz, CA) and 5 µl (
300,000 dpm)
[35S]Met-RGS2-HA, [35S]Met-pcDNA III, or
[35S]Met-luciferase protein were incubated in PBS-0.1%
Triton X-100 with continuously mixing at room temperature for 30 min
before adding a 1:1000 dilution of Gs
antiserum (Santa Cruz Biotechnology). The mixture was
incubated at room temperature for an additional 30 min; then 50 µl of
a 50% slurry of protein A-Sepharose 6 MB beads (Pharmacia) was added,
and the incubation was continued for 2 h. The beads were washed
twice in PBS-0.1% Triton X-100 before the addition of 50 µl sample
buffer (2% SDS containing 10% ß-mercaptoethanol) in preparation for
SDS-10% PAGE. The gels were dried, and the location of
[35S]Met-RGS-HA was determined after exposure to x-ray
film for 24–48 h.
To further assess RGS2-Gs binding, L293 cells
were transfected with RGS2-HA DNA using the Lipofectamine method. L293
cells were chosen for their high transfection efficiency. Two days
after transfection, L293 cells were incubated with or without
10-7 M GIP for 30 min. Cells were then
pelleted and lysed in a lysis buffer containing 0.4 M NaCl,
50 mM Tris-HCl (pH 7.6), 1 mM EDTA, 1% Triton
X-100, and 10% glycerol, supplemented before use with 0.2
mM phenylmethylsulfonylfluoride, 4 mM
benzamidine, 10 µg/ml leupeptin, and 10 µg/ml aprotinin. The
lysates were then sonicated three times for 30 s each time on ice
and centrifuged at 4 C at 30,000 rpm for 20 min. The supernatants were
incubated at 4 C for 2 h with a 1:500 dilution of HA antiserum
(Berkeley Antibody Co., Richmond, CA) and protein A-Sepharose 6 MB
bead. The beads were washed six times each with 10 vol lysis buffer.
The bound protein was eluted in 2 x SDS sample buffer and
separated on SDS-PAGE gels. After electrophoresis, gels were either
stained with Coomassie brilliant blue or transferred to a Hybond-C
Extra filter (Amersham), and Gs
proteins were detected using Gs antiserum
(Santa Cruz Biotechnology) and the enhanced
chemiluminescence system (Amersham) according to the
manufacturer’s instruction.
Statistics
Results are expressed as the mean ± SE.
Statistical analysis was performed using ANOVA and Student’s
t test. P < 0.05 was considered
statistically significant.
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Results |
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, control). Preincubation with
10-7 M GIP for 10 min completely abolished
subsequent GIP-stimulated cAMP generation (Fig. 1, GIP preincubation).
Cotransfection of RGS1, -3, and -4 with GIP-R did not affect the cAMP
level, whereas RGS2 expression suppressed cAMP production by about 55%
(Fig. 1, RGS2). Expression of GIP-R determined by
[125I]GIP binding (cpm/105 cell) did not
differ among the groups and was as follows: control, 2600 ± 250;
RGS1, 2455 ± 310; RGS2, 2380 ± 225; RGS3, 2720 ± 330;
and RGS4, 2870 ± 260 (mean ± SE of four
experiments, with assay performed in duplicate).
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, pRC/CMV). The
addition of 10-7 M GIP further stimulated
insulin release and resulted in a 2.95-fold increase over the basal
insulin concentration. This incretin effect of GIP was completely
abolished in RGS2-transfected cells, whereas the glucose-stimulated
insulin secretion was well preserved (Fig. 3, RGS2).
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, lane A), or RGS2 (Fig. 4, lane B) and
wild-type L293 cells (Fig. 4, lane C) were examined for the presence of
RGS2 messenger RNA (mRNA) by Northern blot analysis, with a
random-labeled BSTX1 fragment of RGS2 cDNA as a probe. As
shown in Fig. 4, RGS2 mRNA was detected as a single band approximating
1.6 kb in all cells and was more abundant in L293 then in ßTC3
cells.
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protein in vitro, lanes A and C), whereas no visible
band was identified with pcDNA III DNA (lane B), demonstrating the
specificity of the rabbit reticulocyte lysate system. SDS-PAGE analysis
of Gs immunoprecipitants identified a 40-kDa
35S-labeled band (lower panel of Fig. 6, lane A)
in Gs-RGS2-HA, but not in
Gs-pcDNA III or
Gs-luciferase (lanes B and C), recombinant
protein, suggesting an interaction between RGS2 and the -subunit of
the G protein complex. In a separate study, Gs
strongly interacted with RGS2-HA in GIP-stimulated (Fig. 7), but not in unstimulated, L293 cells,
also supporting this conclusion.
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Discussion |
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In this report we present the results of studies suggesting a potential role of RGS2 in governing desensitization of the GIP-R. Our studies demonstrate that overexpression of RGS2 results in an attenuation of GIP-stimulated cAMP production in GIP-R cDNA-transfected L293 cells. This response was not seen in cells cotransfected with RGS1, -3, and -4, indicating a specific role of RGS2 in modulating GIP-induced response. Moreover, this inhibitory effect is not due to the interference of receptor expression by RGS transfection, as all RGS-transfected cells exhibit a similar receptor number. Furthermore, GIP-stimulated insulin release in ßTC3 cells was significantly inhibited by GRS2 expression, whereas glucose-induced insulin secretion was not affected, suggesting a distinct role for RGS2 in modulating GIP-mediated insulin secretion. The presence of RGS2 mRNA message in L293 and ßTC3 cells also supports the role of RGS2 in regulating desensitization of the GIP-R in these cells.
Recently, Pepperl et al. (27) have shown that RGS2, but not RGS4 or RGS7, mRNA was strongly induced in forskolin-stimulated rat pheochromocytoma cells (PC12). Similar to their findings, our study demonstrated a moderate, but significant, increase in RGS2 mRNA in GIP-treated ßTC3 cells at 60 min. These results suggest that RGS transcripts may be regulated by changes in intracellular cAMP levels and are consistent with the idea that agonist-stimulated cAMP production induces RGS2 expression and results in feedback desensitization of the stimulating receptors. However, our study did not reveal a significant change in RGS2 mRNA levels at 30 min, when inhibition of insulin release was observed. Although the rate of RGS2 mRNA degradation was not examined in the current study, it is unlikely that the early effect of RGS2 on insulin secretion is due to an increase in the synthesis of new RGS2 mRNA or protein. The precise function of RGS2 in GIP-mediated insulin release requires further examination.
Our finding that RGS2 binds Gs protein
in vitro suggests the interaction between RGS2 and G protein
complex, a phenomenon also demonstrated in GAIP (28) and Sst2p (26). As
stated above, GIP mediates its end-organ effects primarily through
activation of adenylate cyclase and intracellular calcium signaling
(6, 7, 8). Previous studies establish the presence of
Gs in GIP-R-bearing cells (29) (our
unpublished observation) and the effect of cholera toxin on cAMP
generation (30), supporting the concept that GIP stimulates cAMP
production predominantly through coupling to a
Gs-containing heterotrimeric G protein.
Recently, Neill et al. (18) demonstrated that RGS3 bound to
Gq, but not Gs, and
Berman et al. (19) and Watson et al. (20) showed
that RGS1 and -4 interacted with Gi, but not
Gs. The failure of RGS1, -3, and -4 to inhibit
the GIP-coupled signaling pathway as shown in the present studies is
consistent with a relative specificity of interaction between RGS2 and
Gs. However, recent studies by Heximer
et al. (31, 32) and Chen et al. (33) failed to
demonstrate the binding between RGS2 and Gs in
an in vitro system. Thus, the interaction between RGS and
heterotrimeric G proteins can be cell and/or receptor specific, and
whether RGS2 binds other G proteins warrants further investigation.
Despite elevated serum GIP concentrations, type II diabetic patients were found to have a diminished GIP-mediated insulinotropic effect (5, 6). Although the precise mechanisms regulating GIP release in diabetic patients have not been fully examined, studies suggest that elevated serum glucose might exhibit a stimulatory effect on GIP secretion (34, 35). It is likely that homologous desensitization of the GIP-R in type II diabetic patients could contribute to the impairment of insulin secretion in these patients, and the findings of the present study indicate that RGS2 may potentially modulate this process. These hypotheses, however, based on cell studies in vitro may not reflect the in vivo mechanism. Furthermore, the effects of overexpression of RGS2 on cAMP production and insulin release in the current study may not be observed in native islet cells. Thus, to establish the role of RGS2 in GIP-induced desensitization, more studies are needed to demonstrate that ablation of RGS2 in pancreatic islets hinders desensitization of the GIP-R.
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Footnotes |
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Received February 13, 1998.
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References |
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proteins and inhibits pheromone signaling in yeast. J Biol Chem 272:8679–8685This article has been cited by other articles:
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