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Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
1 Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
(Requests for offprints should be addressed to A Tanoue; Email: atanoue{at}nch.go.jp)
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Abstract |
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Introduction |
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AVP- and OT-induced pancreatic hormone secretion, such as insulin and glucagon, is evoked by the activation of AVP and OT receptors expressed in pancreatic islet cells. These AVP and OT receptors are seven transmembrane G-protein-coupled receptors and belong to the same family. This receptor family consists of the V1a, V1b, and V2 receptors and the OT receptor. Several studies have reported that the V1b and OT receptors are involved in insulin and glucagon secretion from a pancreatic cell line (Richardson et al. 1995, Yibchokanun & Hsu 1998) or isolated islets (Oshikawa et al. 2004). While insulin secretion by AVP (Richardson et al. 1995, Oshikawa et al. 2004) and OT (Lee et al. 1995) has been shown to be induced via the V1b receptor, previous studies with subtype-nonselective vasopressin receptor antagonists suggested that both the V1b and the OT receptors were involved in glucagon secretion by stimulation with AVP and OT (Yibchok-anun & Hsu 1998, Yibchok-anun et al. 1999). Although both V1b and OT receptors are involved in the glucagon secretion, no one has analyzed this secretion when specific receptor is absent.
To elucidate the roles of the V1b receptor in glucagon secretion, we examined the mechanism of AVP- and OT-induced glucagon secretion using receptor-selective antagonists and V1b receptor knockout (V1bR–/–) mice (Tanoue et al. 2004), in which tissue expression of the V1b receptor mRNA was undetectable (Oshikawa et al. 2004). First, we examined whether SSR149415, a recently developed V1b receptor-specific antagonist (Serradeil-Le Gal et al. 2002, Folny et al. 2003, Oshikawa et al. 2004), inhibited AVP- and OT-induced glucagon secretion from primary cultured mouse islet cells. We next investigated the involvement of the OT receptor in AVP- and OT-induced glucagon secretion using d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH29]OVT (CL-14-26), an OT receptor-selective antagonist. Furthermore, we investigated glucagon secretion in V1bR–/– mice with the antagonists. We show here that both the V1b and the OT receptors fundamentally mediate AVP- and OT-induced glucagon secretion respectively, and that signaling pathways through the OT receptor can mediate and compensate AVP-induced glucagon secretion when the V1b receptor is completely abolished.
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Materials and Methods |
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Fetal bovine serum (FBS) was from Thermo Trace (Melbourne, Australia). Hanks’ solution was from Nissui (Tokyo, Japan). AVP and OT were from the Peptide Institute (Osaka, Japan). [3H]AVP ([Arg8]-vasopressin, [phenylalanyl-3,4,5-3H(N)]; specific activity, 60.0 Ci/ mmol) and [3H]OT (OT, [tyrosyl-2,6-3H]; specific activity, 48.0 Ci/mmol) were from Perkin–Elmer Life and Analytical Sciences (Boston, MA, USA). SSR149415, which was the specific antagonist for the V1b receptor, was donated by Sanofi-Synthelabo (Montpelier, France). d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH29]OVT (CL-14-26), which specifically antagonized the OT receptor (Elands et al. 1988, Kawamata et al. 2003), was a generous gift from Dr Maurice Manning (Medical College of Ohio). The RPMI 1640 medium, BSA, and diethylstilbestrol dipropionate (DES) were purchased from Sigma-Aldrich (Tokyo, Japan). Collagenase S-1 was purchased from Nitta (Osaka, Japan). Glucagon ELISA kits and all other chemicals were purchased from WAKO (Tokyo, Japan).
Animals
Male mice deficient in the V1b vasopressin receptor were generated by gene targeting as described previously (Tanoue et al. 2004). Briefly, by homologous recombination, we disrupted exon 1, which contains the translation initiation codon. The generated mutant mice were of a mixed genetic background of 129Sv and C57BL/6. For this study, wild-type (V1bR+/+) mice were used as controls and maintained on the 129Sv and C57BL/6 genetic background. All animals used in this study were 9–10 weeks old. Mice were housed in micro-isolator cages in a pathogen-free barrier facility (12 h light:12 h darkness cycle) with access to regular chow and water available ad libitum. All experiments followed the institutional guidelines.
Isolation of pancreatic islets and glucagon measurement
Mouse pancreatic islets were isolated from male mice by collagenase digestion followed by Ficoll gradient separation as described previously (Shibata et al. 1976, Oshikawa et al. 2004). Briefly, the mouse pancreas was injected with an aliquot of 3 ml Hanks’ medium containing 2 mg/ml collagenase S-1 through the choledoch duct by clamping one side of the duct to block the flow into the intestinal tract. Pancreata were collected from four to five mice, and incubated at 37 °C for 20 min. The reaction was stopped by the addition of ice-cold Hanks’ medium. The digested pancreata were washed with the same medium, filtrated through a Spectra-mesh (408 µm; Spectrum Laboratories, Inc., Ft. Lauderdale, FL, USA), and washed with the same medium. The samples were resuspended in 4 ml Ficoll (specific gravity, 1.22) and then overlaid twice with 2 ml Ficoll with specific gravities of 1.09 and 1.05. After centrifugation at 2000 g for 10 min, the islets were collected from the interface. The isolated islets were washed with an RPMI 1640 medium containing 10% FBS, 11 mM glucose, 50 U/ml penicillin, and 50 µg/ml streptomycin and pre-incubated for 2–3 h in the same medium at 37 °C in 5% CO2. Fifteen islets were used for one assay, and experiments including three or four assays in one dose were repeated four to five times. After sampling of the baseline, AVP or OT stimulation was performed at 37 °C for 10 min. Arginine (20 mM) was used as a positive control. Each antagonist was added 5 min before the stimulation with AVP or OT. After stimulation, the supernatant was taken up and the glucagon concentration was measured using the glucagon ELISA kit.
Ligand binding assay
Uterine tissues were isolated from female mice treated with DES (0.3 mg/kg body weight) i.p., 20 h before isolation. Uterine cells stably expressing mouse V1b receptor were prepared as described previously (Oshikawa et al. 2004). Saturation binding studies were performed to incubate 20 µg cell membrane and 50 µg uterine membrane preparations with various concentrations of [3H]AVP and [3H]OT (0.1–5.0 nM) in 250 µl assay buffer containing 50 mM Tris–HCl (pH 7.4), 10 mM MgCl2, and 0.05% BSA. For competition binding studies, 1 nM [3H]AVP and 2 nM [3H]OT were added to cell membrane and uterine membrane preparations respectively, and incubated with various concentrations of compounds in 250 µl assay buffer. The incubation condition in all binding studies was 1 h at room temperature. The reaction was stopped by an ice-cold wash buffer containing 50 mM Tris–HCl (pH 7.4) and 5 mM MgCl2, filtered onto UniFilter-96 GF/C using a FilterMate Cell Harvester (Perkin–Elmer Life Science and Analytical Sciences). The filters were rinsed five times, and the radioactivity was measured using a TopCount Microplate Scintillation Counter (Perkin–Elmer Life Science and Analytical Sciences). Non-specific binding was determined using 1 µM unlabeled AVP and OT. Specific binding was calculated as the difference between total and nonspecific counts. The inhibitory Kd values (Ki) were calculated using the following formula (Cheng & Prusoff 1973): Ki = IC50(1+[L]/KD), where IC50 is the concentration of the test compound that caused 50% inhibition of specific binding, [L] is the concentration of the radioligand present in the assay, and KD is the Kd of the radioligand obtained from Scatchard plotting. The binding data were analyzed by the iterative nonlinear regression program, LIGAND (Munson & Rodbard 1980).
Statistical analysis
Data are expressed as means ± standard error (S.E.M.). Statistical analysis was performed using the unpaired Student’s t-test and the one- or two-way ANOVA followed by a post hoc comparison with Fisher’s probable least-squares differences (PLSD) test using Statview version 5.0 software (Concepts, Inc., Berkeley, CA, USA). Differences between groups were considered statistically significant at the level of P<0.05.
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Results |
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AVP increased glucagon secretion from the islets of V1bR+/+ mice in a dose-dependent manner (Fig. 1A
). AVP-induced glucagon secretion in V1bR+/+ mice was five times the value at the baseline after stimulation of 10–8 M, which was a sufficient concentration to release glucagon under the conditions of this experiment (glucagon secretion at 10–8 vs 10–7 M of AVP, P = 0.39). The basal glucagon concentration was 355.1 ± 59.4 pg/µl in AVP-stimulation experiments. OT-induced glucagon secretion was six times that at the baseline at 10–7 M, which was a sufficient concentration to release glucagon in V1bR+/+ mice (the glucagon secretion at 10–8 vs 10–7 M AVP, P<0.01; Fig. 1B). Basal glucagon concentration was 386.7 ± 47.4 pg/µl in OT-stimulation experiments. Glucagon secretion by arginine stimulation in this experiment was approximately four times that at the baseline and lower than that by AVP or OT stimulation (Fig. 1).
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Antagonists were used to identify the receptors involved in glucagon secretion from the islets of V1bR+/+ mice. We selected and used SSR149415 as a V1b receptor-specific antagonist that was used in a previous experiment (Oshikawa et al. 2004). In this study, we examined the specificity of CL-14-26 for a mouse OT receptor using a radioligand binding assay using the uterine plasma membrane of female mice treated with DES. The Bmax was 0.4 ± 0.02 and 0.1 ± 0.01 pmol/mg protein for the cell membrane expressing the V1b receptor and the uterine membrane respectively. The KD values were 0.3 ± 0.1 and 0.5 ± 0.07 nM, as obtained from Scatchard plot analysis (n = 3 in each experiment). The results of the competition binding analysis using AVP, OT, and antagonists are shown in Table 1. The data showed that CL-14-26 was a selective antagonist for the OT receptor rather than the V1b receptor, with Ki values of 83 ± 6.1 (n = 4) and 7800 ± 0.8 (n = 4) nM for the OT and the V1b receptors respectively.
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). Around 30% inhibition was observed at 10–6 M SSR149415, whereas, from 10–9 to 10–6 M, CL-14-26 could not significantly inhibit AVP-induced glucagon secretion from the islets of V1bR+/+ mice (Fig. 2B). Furthermore, the OT-selective antagonist, CL-14-26, significantly inhibited OT-induced glucagon secretion from the islets of V1bR+/+ mice at 10–6 M (Fig. 2C). Around 45% inhibition was observed at 10–6 M CL-14-26, whereas 10–6 M SSR149415 tended to suppress OT-induced glucagon secretion, but not significantly (Fig. 2C). These results indicated that AVP and OT stimulated glucagon secretion through the V1b and OT receptors respectively, in V1bR+/+mice.
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). The percentage inhibition of SSR149415 in AVP-induced glucagon secretion was increased from 30 to 57% in combination with CL-14-26. Similarly, the percentage inhibition of SSR149415 in OT-induced glucagon secretion was increased from 45 to 69% in combination with CL-14-26. There were no significant differences between the basal levels and either AVP or OT stimulation in combination with both SSR149415 and CL-14-26 (one-way ANOVA; P = 0.52 in AVP stimulation, P = 0.33 in OT stimulation). These results suggested that AVP could stimulate glucagon secretion via the OT receptors, when the V1b receptor was blocked by SSR149415; and that OT could also stimulate it via the V1b receptors, when the OT receptor was blocked by CL-14-26. AVP- and OT-induced glucagon secretion from the islets of V1bR–/– mice
We examined AVP- and OT-induced glucagon secretion from the islets of V1bR–/–mice (Fig. 3). Not only OT but also AVP was able to stimulate glucagon secretion in V1bR–/– mice in a dose-dependent manner, as observed in V1bR+/+ mice (Fig. 3A and B). In V1bR–/– mice, AVP- and OT-induced glucagon secretion was about six times that at the baseline at 10–7 M, which was a sufficient concentration to release glucagon under the conditions of this experiment (glucagon secretion at 10–8 vs 10–7 M AVP, P<0.05; glucagon secretion at 10–8 vs 10–7 M OT, P<0.01). The basal glucagon concentrations were 340.8 ± 52.7 and 339.5 ± 20.8 pg/µl in AVP- and OT-stimulation experiments respectively. There were no significant differences in AVP- and OT-induced glucagon secretion between V1bR+/+ and V1bR–/– mice (V1bR+/+ mice versus V1bR–/– mice; P = 0.85 for AVP-stimulation experiments, and P = 0.81 for OT-stimulation experiments by two-way ANOVA). Glucagon secretion by arginine stimulation in this experiment was approximately four times that at the baseline and lower than that by AVP or OT stimulation, similar to the observation in V1bR+/+ mice (Fig. 3). These findings suggested that AVP could stimulate glucagon secretion via a receptor(s) other than the V1b receptor in V1bR–/– mice as potently as OT could.
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). In particular, CL-14-26 could almost completely inhibit AVP-induced glucagon secretion at a concentration of 10–6 M in V1bR–/– mice, whereas it did not significantly antagonize AVP-induced glucagon secretion in V1bR+/+ mice. There were no significant differences between the basal level and either AVP or OT stimulation in combination with CL-14-26 in V1bR–/– mice (one-way ANOVA; P = 0.50 in AVP stimulation, P = 0.12 in OT stimulation). This suggested that AVP and OT stimulate glucagon secretion through the OT receptor in V1bR–/– mice, in which a signaling pathway of the OT receptors could achieve optimal efficacy by stimulation of even OT and AVP.
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). These findings indicated that the effect of simultaneous stimulation of both AVP and OT was additive in V1bR+/+ mice but not in V1bR–/– mice, suggesting that AVP and OT secreted glucagon through a single pathway, i.e. the OT receptor-mediating pathway, in V1bR–/– mice.
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Discussion |
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The analysis of V1bR–/– mice has revealed that AVP could sufficiently stimulate glucagon secretion under the V1b receptor-deficient condition, since AVP stimulated glucagon secretion as potently in V1bR–/– mice as in V1bR+/+ mice. AVP-induced glucagon secretion in V1bR–/– mice was inhibited by the OT receptor antagonist but hardly affected AVP-induced glucagon secretion in V1bR+/+ mice. These findings indicated that AVP-induced glucagon secretion via the OT receptors could be activated in V1bR–/– mice. Thus, our study implicated that there was a cross-reactivity of AVP to the OT receptor on releasing glucagon and that switching from the V1b to the OT receptors would take place under the V1b receptor-deficient condition. This is the first time that the existence of a compensating system between the V1b and the OT receptors has been revealed. On the other hand, OT has been reported to stimulate glucagon secretion via the V1b receptor in In-R1-G9, a hamster clonal 
cell line (Yibchokanun & Hsu 1998). Because this cell line has low affinity for OT (Folny et al. 2003), which indicates that the OT receptors could be rarely expressed in this cell line, the signaling pathways via the V1b receptors on OT-induced glucagon secretion could be activated in this cell line. Thus, it is likely that the compensating mechanisms between the V1b and the OT receptors could be interchangeable and that AVP and OT could have different efficacy to the V1b and the OT receptors depending on their population and predominance.
In conclusion, our studies with mutant mice and receptor-selective antagonists clearly demonstrate that AVP and OT may induce glucagon secretion through a dual pathway, which is mediated by either the V1b and OT receptors or the OT receptor in the case of V1b receptor deficiency. The plasma concentration of AVP and OT is approximately 10–12 M in humans (Baylis et al. 1981, Volpi et al. 1998). Since 10–9–10–7 M AVP and OT was used in the present study, it is unlikely that glucagon secretion occurred via the V1b and OT receptor stimulation under normal conditions. However, when diseases such as severe septic shock and congestive heart failure occur, it is known that the plasma AVP level increases approximately 10–11–10–9 M (Riegger et al. 1982, Lodha et al. 2006). In addition, i.v. injections of AVP and OT induce glucagon secretion in humans (Spruce et al. 1985). Thus, the cross-reactivity of V1b and OT receptors may be physiologically relevant in some severe disease cases. Our results suggest that it is necessary to consider the possibility that a substitution by other receptors of the same family is caused by the regulation of one receptor. The selective drugs targeting these two receptors could control glucagon secretion, contributing to the regulation of the blood glucose level as novel therapeutic agents.
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Acknowledgements |
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Funding |
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References |
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Received in final form 13 November 2006
Accepted 15 November 2006
Made available online as an Accepted Preprint 15 November 2006
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P<0.001 versus baseline in each stimulation by a one-way ANOVA post hoc comparison with Fisher’s PLSD.
P<0.001 versus vehicle treatment by a one-way ANOVA post hoc comparison with Fisher’s PLSD.
