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Department of Endocrinology and Chemical Biology, Merck Research Laboratories, Merck & Co., Inc. (S.W.M., L.C., E.H., F.F., J.M.S.), Rahway, New Jersey 07065; the National Institute of Neurological Disorders and Stroke, Basic Neuroscience Program, National Institutes of Health (E.M., B.H.), Bethesda, Maryland 20892; and the Department of Integrative Biology and Pharmacology, University of Texas Health Sciences Center (Y.W., A.S.), Houston, Texas 77030
Address all correspondence and requests for reprints to: Dr. Sudha Warrier Mitra, Department of Endocrinology and Chemical Biology, Merck Research Laboratories, R80Y-310, P.O. Box 2000, Rahway, New Jersey 07065. E-mail: sudha_mitra{at}merck.com
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-cells and inhibits the secretion
of both insulin and glucagon. SRIF initiates its actions by binding to
a family of six G protein-coupled receptors (sst1, -2A, -2B, -3, -4,
and -5) encoded by five genes. Messenger RNA for both sst2 and sst5
have been reported in the rat pancreas, and the sst2A receptor protein
has been localized to rat pancreatic 
and pancreatic
polypeptide-secreting cells in the islets as well as to pancreatic
acinar cells. In this study we have used double immunostaining to show
that the sst5 protein is expressed exclusively in the ß-cells of rat
pancreatic islets and localizes with insulin-secreting -cells. The
sst5 receptor is not colocalized with sst2A. Thus, in the rat SRIF
inhibits pancreatic insulin and glucagon secretion via different sst
receptor subtypes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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By using sensitive RT-PCR analysis, Raulf et al. (5)
demonstrated the presence of all sst subtypes in whole rat pancreas
except sst-4. Immunohistochemical localization of sst2A to the
glucagon-containing -cells in rat pancreas (6) suggests that this
receptor subtype has a role in regulating glucagon release in the rat.
This hypothesis is consistent with the report of Rossowski and Coy (7),
which demonstrated that moderately selective sst2A ligands lower serum
glucagon levels in rats. Sst5-selective agonists were reported to lower
serum insulin levels (7). These data suggest that sst5 may be
associated with the insulin-containing ß-cells of the pancreatic
islet. Only recently have agonists with subtype selectivity for binding
greater than 100-fold become available (8). In this study we have
characterized an sst5-selective antibody and used it to determine the
distribution of sst5 in the rat pancreas.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell lines
CHO-K1 cells were obtained from American Type Culture Collection (Manassas, VA) and were grown in MEM supplemented
with penicillin, streptomycin, fungizone, 10 mM HEPES, and
10% FBS. Stably transfected CHO-DG44 cells expressing mouse sst1–3
were obtained from Drs. Terry Reisine (University of Pennsylvania,
Philadelphia, PA) and Graeme I. Bell (University of Chicago, Chicago,
IL). These cells were maintained in the above media containing
geneticin (G418) at 500 µg/ml. Rat sst4 and sst5 complementary DNA
(cDNA) clones were provided by Dr. John Bruno (State University of New
York, Stony Brook, NY). CHO-K1 cells expressing the
haemagglutinin (HA) epitope-tagged rat sst5 receptor were
provided by Dr. Kerry Koller (9).
Transfection
CHO-K1 cells were stably transfected with cloned cDNA encoding
rat sst4, rat sst5, or human sst5 inserted into pcDNA3.1 vectors using
lipofectamine, and G418-resistant clones were selected. Cells were
assayed for receptor expression in a whole cell binding assay, and
those populations expressing receptor were enriched by two cycles of
recloning. Single clonal isolates were obtained by limiting dilution.
Cells expressing each sst were maintained in medium containing G418
(500 µg/ml).
Whole cell binding assay
Selected clones were evaluated for the expression of each sst in
a whole cell binding assay. Each clone was plated into four replicate
wells of a View Plate-96 (Packard Instrument Co., Meriden,
CT) and grown to confluence in the selection medium. The medium was
aspirated, and the cells were washed once with 50 mM
Tris-HCl, pH 7.8, containing 1 mM EGTA, 5 mM
MgCl2, and 0.1% BSA (buffer A) and maintained in buffer A
at room temperature for 30 min. This buffer was aspirated and replaced
with buffer B (buffer A containing 1 mg/ml bacitracin). For the
selection of rat sst4 clones, duplicate wells were incubated with
buffer B containing 1.0 nM
3-[125I]Tyr11-SRIF-14 (SA, 2000 Ci/mmol;
Amersham, Arlington Heights, IL) with or without 1
µM unlabeled SRIF-14. For the selection of rat and human
sst-5 clones, similar incubations were carried with
3-[125I]Tyr25-SRIF-28
(Leu8-DTrp22-Tyr25) at
0.3 nM in the presence or absence of 1 µM
SRIF-28 (Sigma Chemical Co.). After a binding incubation
at room temperature for 30 min, the cells were washed three times with
buffer A and then air-dried. The cells were solubilized by the addition
of 25 µl 1% SDS in 0.1 N NaOH to each well and then 200
µl MicroScint-40 scintillation fluid (Packard, Downers Grove, IL).
Radioactivity was determined in a scintillation counter (Packard).
Membrane preparation
Membranes from cell lines and pancreatic tissue for immunoblot
analysis were prepared as previously described (10). Briefly, cells and
tissue were homogenized using the Tissue Tearor Homogenizer
(Fisher Scientific, Pittsburgh, PA) in buffer C(10
mM Tris-HCl (pH 7.8), 5 mM EDTA, 3
mM EGTA, 250 mM sucrose, 1 mM
phenylmethysulfonyl fluoride (PMSF), 10 µg/ml aprotinin, 50 µg/ml
bacitracin, 10 µg/ml soybean trypsin inhibitor, and 10 µg/ml
leupeptin). Unbroken cells and nuclei were removed by centrifugation at
500 x g for 5 min, and membranes were centrifuged at
10,000 x g for 30 min.
Antibody preparation
The peptide CAIEPRPDKSGRPQAT (representing the C-terminal amino
acids 332–346 of rat sst5 with an added cysteine at the N-terminal end
to facilitate conjugation) was conjugated to keyhole limpet hemocyanin
using m-maleimidobenzoyl-n-hydroxysuccinimide and
used to immunize chickens. Custom peptide synthesis and custom antibody
production were performed by Bio-Synthesis, Inc.
(Lewisville, TX). This sequence is present in rat and mouse sst5, but
not in sst1, sst2A, sst3, or sst4 (Fig. 1
). The homologous region of human sst5
has a contiguous stretch of five identical residues. Eggs were
collected from chickens at times when serum showed high antibody
titers. The yolks were stored in 1:1 PBS (0.0017 M
KH2PO4, 0.005 M
Na2HPO4, pH 7.4, and 0.15 M NaCl)
containing 0.05% sodium azide.
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Peptide affinity columns were prepared by covalently linking the peptide, synthesized as multiple antigenic peptide (MAP) (Research Genetics, Inc., Huntsville, AL) to Ultralink-Carboxyl supports [2 mg peptide/2 ml packed column, with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide] as recommended by the manufacturer and stored in PBS containing 0.05% azide. Columns were washed with 15 vol PBS, and total crude antibody was incubated with the support (15 mg/ml column) for 3–6 h at room temperature. Nonspecifically bound proteins were removed by washing with 20 vol PBS. Specific antibody was eluted with 5 ml 0.1 M triethylamine-HCl, pH 11.5. The eluate was dialyzed against PBS and concentrated to 1 ml by centrifugation through a Biomax filter 10,000 (Millipore Corp., Bedford, MA). Affinity-purified antibody was stored at 4 C in PBS containing 0.05% azide and was designated SWM-479. Enzyme-linked immunosorbent assays (ELISAs) were performed using (Pierce Chemical Co.) starter kit ELISA according to the manufacturer’s instructions. Two hundred and fifty nanograms of the immunogenic peptide (synthesized as MAP) was bound to each well of an Immulon 2 microtiter plate and incubated at room temperature with SWM-479 antibody fractions. The amount of primary antibody bound was determined by incubation with 10 ml of a 1:2000 dilution of horseradish peroxidase (HRP)-conjugated rabbit antichicken antibody (Cappel Laboratories) and developed with diaminobenzidine (Pierce Chemical Co.).
Immunoadsorption of ligand-bound receptor
Equal volumes (10 µl) of affinity-purified anti-sst5 antibody
were bound to microtiter wells, (Immulon) in carbonate buffer (0.2
M carbonate/bicarbonate buffer, pH 9.4; ELISA starter kit,
Pierce Chemical Co.). The wells were preincubated with PBS
containing 1% BSA to prevent nonspecific binding. Appropriate wells
were incubated with either 50 µg antigenic MAP peptide
AIEPRPDKSGRPQAT or the unrelated MAP peptide, PCQQEPMQAEPAC.
Cross-linking of radiolabeled SRIF to receptor was carried out as
previously described (10) with minor modifications. Briefly, membranes
prepared from CHO-K1-derived stable cell lines expressing sst4 and sst5
were incubated with 3-[125I]Tyr25-SRIF-28
(Leu8-DTrp22-Tyr25) at
1 or 3 nM, respectively, in the presence or absence of
unlabeled SRIF-28 at 1 µM. The samples were centrifuged
at 96,000 x g for 1 h, and the unbound label
remaining in the supernatant was discarded. Bound ligands were
cross-linked in the presence of
N-5-azido-2-nitrobenzoyloxysuccinimide at 30
µM using UV irradiation for 10 min at a distance of 8 cm.
Membranes were solubilized with DßM at 4 mg/ml and cholesteryl
hemisuccinate at 200 µg/ml in PBS, and insoluble material was removed
by centrifugation at 96,000 x g. Equal amounts
(
78,000 cpm) of radiolabeled solubilized membrane proteins were
added to each well and incubated overnight at 4 C. After incubation
with receptor, wells were washed four times with 200 µl PBS
containing 1% BSA and 0.1% Tween-20. The wells were allowed to dry,
and bound receptor was solubilized with 1% SDS and 0.1 M
sodium hydroxide and counted in the Packard 
-counter.
Immunoblot analysis
Proteins in membrane extracts were reduced and denatured by
incubation at 37 C for 30 min in sample buffer [32 mM
Tris-HCl (pH 6.8), 0.5% SDS, 12.5% glycerol, 0.01% bromophenol blue,
Bio-Rad Laboratories, Inc.] containing 10%
mercaptoethanol and 5 M urea, separated by PAGE on 4–15%
gradient gels, and transferred to polyvinylidene difluoride membranes,
in transfer buffer (10 mM sodium bicarbonate, 3
mM sodium carbonate, 0.1% SDS, and 20% methanol).
Transferred proteins were immunoblotted as previously described (10).
Briefly, polyvinylidene difluoride membranes were preincubated for
2 h with blocking buffer (10% nonfat dry milk, 10% glycerol, and
0.2% Tween-20 in PBS) and incubated overnight at 4 C with a 1:2500
dilution of SWM-479. Nonspecifically bound antibody was removed by
repeated washing with blocking buffer, followed by incubation for
1 h at room temperature with a 1:2000 dilution of rabbit
HRP-conjugated antichicken antibody (Cappel Laboratories). The
membranes were washed alternately with PBS with and without 1% IGEPAL
(Sigma Chemical Co., St. Louis, MO) developed with ECL
substrates.
Tissue preparation for immunohistochemistry
For immunohistochemistry, four adult male Sprague Dawley rats
(Taconic Farms, Inc., Germantown, NY; 250–300 g) were
perfused with 4% paraformaldehyde (Polysciences, Warrington, PA) in
PBS at 4 C as described previously (12). The pancreas was removed;
postfixed with the same fixative for 30 min; cryoprotected with 5% (2
h), 10% (4 h), then 20% (overnight, at 4 C) sucrose in PBS; and
frozen in 2-methylbutane (Aldrich, Milwaukee, WI).
Ten-micron thick sections were cut in a cryostat, then thaw-mounted,
air-dried at 37 C onto silanized slides, frozen, and stored at -80 C
until used.
Unless otherwise noted, all the procedures were performed at room temperature (20 C). NIH Guidelines for Animal Care and Use were followed in all animal procedures (http://intramural.nimh..nih.g/icmr/snge).
Immunohistochemical/immunocytochemical methods
Immunofluorescent double labeling (13) was used for cellular
colocalization of sst5 receptor with insulin, glucagon, SRIF,
pancreatic polypeptide, and the sst2A receptor. For
immunohistochemistry all primary and secondary antibodies were diluted
in BSA-diluent (PBS, containing 1% BSA and 0.6% Triton X-100). The
specification and the dilution of the primary and secondary antibodies
are listed in Tables 1 and 2 (6, 12, 13, 14, 15, 16, 17, 18).
The steps of the double immunolabeling were as follows, with three 5-min washes in PBS between steps: 1) postfixation in 4% formaldehyde fixative for 10 min, 2) blocking of nonspecific staining with BSA-diluent for 30 min, 3) incubation with the antiserum to sst5 receptor overnight at 4 C, 4) incubation with Cy3-conjugated antichicken IgY for 1 h, 5) incubation with the second primary antibody raised in rabbit (glucagon, SRIF, and pancreatic polypeptide) or guinea pig (insulin), and 6) incubation with fluorescein isothiocyanate (FITC)-conjugated antirabbit or antiguinea pig IgG for 1 h.
The tyramide signal amplification (TSA) method (NEN, Boston, MA) was used to label sst2A receptor (6). The manufacturer’s protocol was followed in this procedure as detailed in our previous papers (6, 13). Steps of this labeling after 1) postfixation and 2) blocking were: 3) incubation with the primary antibody to sst2A overnight at 4 C, 4a) incubation with FITC-conjugated antirabbit IgG secondary antibody for 1 h, 4b) incubation with HRP-conjugated anti-FITC antibody for 1 h, and 4c) final signal amplification using tyramide-FITC conjugate for 10 min. The subsequent immunolabeling for sst5 was completed as described above.
SRIF receptor-transfected CHO-K1 cells were tested for sst5 receptor according to steps 1–4 of the immunohistochemical protocol. After immunostaining, the sections were washed in distilled water, air-dried, and coverslipped using Cytoseal 60 medium (Stephens Scientific, Riverdale, NJ). Immunofluorescent labeling was viewed with a fluorescent microscope (Dialux 20, Leitz Co., Stuttgart, Germany) using fluorescent filters for FITC (appears green) and Cy3 (appears red). Photomicrographs were taken using an Axiphot fluorescent microscope (Carl Zeiss, Oberkochen, Germany). Double color images were generated using a double pass fluorescent filter, allowing detection of both FITC-green and Cy3-red. Color figures were mounted and printed using a slide scanner (Lacie Silverscanner III, Seiko Epson, Nagano, Japan) and Adobe Photoshop 3.0 software ( Mountain View, CA) with 400-2500 dpi resolution.
Immunohistochemical controls
Preabsorption of the antibody to sst5 receptor with 100 µg/ml
immunizing receptor peptide (4 C, overnight) completely abolished the
signal in pancreatic islet cells. Preabsorption with 10 or 1.0 µg/ml
receptor peptide resulted in incomplete signal reduction. CHO-K1 cells
transfected with the individual SRIF receptor subtypes (sst1–5) were
used to verify the specificity of the sst5 antibody. The antibody
selectively labeled the cells transfected with the rat sst5 receptor
(not shown). The signal in sst5 receptor-transfected cells was
abolished by preabsorption of the antibody with 100 µg/ml immunizing
receptor peptide.
We used fluorochrome-labeled affinity-purified F(ab)2-fragment IgY and IgG secondary antibodies, developed in donkey (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA). The appropriate species recognition of these secondary antibodies was confirmed in our hands by the lack of specific labeling in controls when noncorresponding secondary antibodies were used after the primary antibody.
Further controls included immunostaining with the primary antibodies substituted by nonimmune sera, nonimmune IgGs, or BSA diluent in step 3. Finally, all of the double immunostainings gave identical results when we reversed the order of the primary antibody incubations.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, lane 1). The
presence of a 1000-fold excess of unlabeled SRIF-28 during binding
incubation reduced the counts bound to the antibody by 20-fold compared
with that in membranes labeled in the absence of competing ligand (lane
2). Preincubation of the SWM-479 antibody with antigenic peptide (as
MAP) virtually eliminated immunoadsorption of the receptor-ligand
complex, whereas preincubation with a nonantigenic peptide failed to
prevent immunoadsorbtion (lane 4). There was only negligible adsorption
of radiolableled sst4 membrane extracts (lane 5). These
immunoadsorption studies show that SWM-479 recognizes functional sst5
receptor, but fails to recognize functional sst4 receptor.
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, lane 7). Preadsorption of the antibody
with the antigenic peptide blocked both of these interactions (lane 8).
Anti-HA antibody reacted with the 50-kDa protein, but not with the
32-kDa protein (data not shown), suggesting that the latter is a
proteolysis product containing the C-terminal, but not the N-terminal,
region of the sst5 receptor. The sst5 antibody failed to detect any
immunoreactive proteins in membrane extracts from untransfected CHO-K1
cells (lane 1) or membrane extracts from CHO-K1 cells transfected with
mouse sst1, -2, or -3 or rat sst4 (Fig. 3, lanes 2–5). The sst5
antibody also failed to recognize any proteins from cells transfected
with human sst5 (lane 6). We conclude that SWM-479 specifically
recognizes the rat sst5 receptor.
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). Preadsorption of the antibody with
the antigenic peptide abolished the labeling in pancreatic islets (Fig. 4P). All sst5 staining colocalized with insulin (Fig. 4, A–C).
Glucagon-, SRIF-, and pancreatic polypeptide-immunoreactive cells were
not labeled by the sst5 antibody (Fig. 4, D–L). Double immunostaining
showed no colocalization between sst2A and sst5 receptor labeling (Fig. 4, M–O). According to our previous report (6), sst2A receptor is
expressed in exocrine cells and in certain peripheral islet cells, such
as glucagon-producing A cells and pancreatic polypeptide-producing
cells but not in SRIF-producing D cells. In contrast, here we
demonstrate that sst5 immunoreactivity is localized to
insulin-producing ß-cells in the center area of rat pancreatic
islets.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and reported previously (6). In addition, the
peptide used to generate the antibody is not represented anywhere in
the rat or mouse sst1–3. We, therefore, believe we are justified in
substituting mouse sst1, -2, and -3 for rat sst1, -2, and -3.
Competition by the antigenic peptide further confirms the selectivity
of the antibody.
Our immunohistochemical studies complement previous work demonstrating
the localization of sst2A on glucagon-containing -cells (6) and
reports of sst5 messenger RNA in rat pancreas (5) and are also
consistent with the report of Rossowski et al. (7), in which
moderately selective sst5 agonists were reported to lower insulin
levels in the rat. However, our observations are not in agreement with
those reported by Moldovan et al. (19), who have reported
that the sst2A-selective compound inhibits insulin release from human
pancreatic islets using a perfusion system. The subtype selectivity of
the compound used in these experiments, DC-32–87, is somewhat
controversial, and other groups have reported that this compound has
high affinity for sst2, -3, and -5, which might explain the differences
in our results (20, 21). Another possibility is the different
localization of ssts in different species. Species-specific differences
in sst messenger RNA distribution between rodent and human tissues are
well documented. For instance, sst2 message is found in human liver,
but not in rat liver (22), whereas sst3 message is detectable in rat
liver, but undetectable in human liver (5, 23). Recently,
immunohistochemistry with anti-sst2A antibodies has indicated that
ß-cells of human pancreatic islets express sst2A, in contrast to
their total absence from ß-cells of rat (24). As a result, great
caution has to be exercised in extrapolating information from animal
models to humans.
Although we were able to detect sst5 protein in immunoblots of extracts from CHO-K1 cells overexpressing rat sst5, we were unable to detect proteins of appropriate size in rat pancreatic membrane extracts. This was probably due to the relatively sparse distribution of sst5-expressing cells in the pancreas. As the sst5-staining cells were located exclusively in the central area of the islets, and the islets represent no more than 1–2% of the pancreas (25, 26), the level of expression in the pancreas is presumably below the level of detection by immunoblotting. Helboe et al. have also reported detecting a broadly migrating band approximately 50 kDa in size in sst5-transfected BHK tk-ts13 cells using antibodies raised against glutathione-S-transferase fusion proteins with C-terminal amino acids (27). They have also detected faster migrating proteins, including one approximately 30 kDa in size. SWM-479 has been reported to detect a 64-kDa band in the rat pituitary (28), which is significantly larger than that seen in CHO-K1 cells overexpressing sst5 receptor. Dournaud et al. reported that in the rat the antipeptide antibody against sst2A detects a broad band at about 85 kDa in CHO-K1 cells expressing sst2A, whereas it detects a broad band of approximately 72 kDa in the rat cortex (14). A similar variation in the size distribution of sst2A has been seen in human pituitary adenoma, which had a broad size distribution of approximately 80 kDa, whereas sst2A in human meningioma was about 60 kDa (29). We attribute this size discrepancy to differential tissue-specific posttranslational modifications.
Subtype-selective SRIF agonists/antagonists may provide a pharmacological approach for the regulation of glucose levels (8). Although differential expression of sst5 on ß-cells suggests that sst5 agonists could directly inhibit insulin secretion in the rat without affecting glucagon secretion, the situation in the human pancreas seems more complicated (29). It is entirely possible that sst5 and sst2 are colocalized in the same ß-cell of the human pancreas. On the other hand, colocalization of more than one receptor on a cell does not preclude independent signaling pathways and, hence, independent regulation. In rat insulinoma 1046–38, which express both sst1 and sst2A, sst1-selective agonists show inhibition of voltage-gated Ca2+ channels, whereas moderately sst2A-selective agonists inhibited adenylyl cyclase activity (30). Sst2A-specific agonists may be effective in inhibiting glucagon secretion without affecting insulin secretion, or alternatively, sst5-specific antagonists alone or in combination with specific sst2A agonists may prove to be promising approaches to the treatment of diabetes and the maintenance of glucose homeostasis. Two endogenous ligands for these receptors are known, SRIF-14 and SRIF-28. Both peptides bind to sst2A with similar affinities. However, SRIF-28 has approximately a 5-fold higher affinity for sst5 than does SRIF-14, suggesting that SRIF-28 may be the endogenous regulator of insulin release from the pancreas.
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Footnotes |
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Received August 6, 1998.
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P. A Smith, L. A Sellers, and P. P A Humphrey Somatostatin activates two types of inwardly rectifying K+ channels in MIN-6 cells J. Physiol., April 1, 2001; 532(1): 127 - 142. [Abstract] [Full Text] [PDF]
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M. Afargan, E. T. Janson, G. Gelerman, R. Rosenfeld, O. Ziv, O. Karpov, A. Wolf, M. Bracha, D. Shohat, G. Liapakis, et al. Novel Long-Acting Somatostatin Analog with Endocrine Selectivity: Potent Suppression of Growth Hormone But Not of Insulin Endocrinology, January 1, 2001; 142(1): 477 - 486. [Abstract] [Full Text] [PDF]
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M. Z. Strowski, R. M. Parmar, A. D. Blake, and J. M. Schaeffer Somatostatin Inhibits Insulin and Glucagon Secretion via Two Receptor Subtypes: An in Vitro Study of Pancreatic Islets from Somatostatin Receptor 2 Knockout Mice Endocrinology, January 1, 2000; 141(1): 111 - 117. [Abstract] [Full Text] [PDF]
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 H. Baumeister and W. Meyerhof The POU Domain Transcription Factor Tst-1 Activates Somatostatin Receptor 1 Gene Expression in Pancreatic beta -Cells J. Biol. Chem., September 8, 2000; 275(37): 28882 - 28887. [Abstract] [Full Text] [PDF]
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