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And Oxytocin-Induced Glucagon Secretion in V1b Vasopressin Receptor Knockout Mice

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And Oxytocin-Induced Glucagon Secretion in V1b Vasopressin Receptor Knockout Mice 361 Mutual regulation of vasopressin- and oxytocin-induced glucagon secretion in V1b vasopressin receptor knockout mice Yoko Fujiwara, Masami Hiroyama, Atsushi Sanbe, Junji Yamauchi, Gozoh Tsujimoto1 and Akito Tanoue Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan 1Department 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: [email protected]) Abstract [Arg8]-vasopressin (AVP) and oxytocin (OT) are neurohy- CL-14-26 further inhibited AVP- and OT-induced glucagon pophysial hormones which exert various actions, including secretions in islets of V1bRC/C mice (57 and 69% of the the control of blood glucose, in some peripheral tissues. To stimulation values respectively). In addition, both AVP and investigate the type of receptors involved in AVP- and OT stimulated glucagon secretion with the same efficacy in OT-induced glucagon secretion, we investigated the effect V1bRK/K mice as in V1bRC/C mice. AVP- and of these peptides on glucagon secretion in islets of OT-induced glucagon secretion in V1bRK/K mice was wild-type (V1bRC/C) and vasopressin V1b receptor significantly inhibited by CL-14-26. These results demonstrate knockout (V1bRK/K) mice. AVP-induced glucagon that V1b receptors can mediate OT-induced glucagon secretion secretion was significantly inhibited by the selective V1b and OTreceptors can mediate AVP-induced glucagon secretion receptor antagonist, SSR149415 (30%), and OT-induced in islets from V1bRC/C mice in the presence of a heterologous glucagon secretion by the specific OT receptor antagonist, antagonist, while AVP and OT can stimulate glucagon secretion ð Þ ½ ð Þ2; 4; 9 d CH2 5 Tyr Me Thr Tyr-NH2 OVT (CL-14-26) through the OTreceptors in V1bRK/K mice, suggesting that C C (45%), in islets of V1bR / mice. AVP- and OT-induced the other receptor can compensate when one receptor is absent. glucagon secretions were not by the antagonist of each, but K K Journal of Endocrinology (2007) 192, 361–369 co-incubation with both 10 6 M SSR149415 and 10 6 M Introduction These AVP and OT receptors are seven transmembrane G-protein-coupled receptors and belong to the same family. Arginine-vasopressin (AVP) and oxytocin (OT) are neurohy- This receptor family consists of the V1a, V1b, and V2 pophysial hormones synthesized in the paraventricular nucleus receptors and the OT receptor. Several studies have reported and supraoptic nucleus of the hypothalamus. AVP acts in many that the V1b and OT receptors are involved in insulin and organs and plays a variety of physiological roles, such as glucagon secretion from a pancreatic cell line (Richardson vasoconstriction (Schrier et al. 1993), glycogenolysis in the et al. 1995, Yibchok-anun & Hsu 1998) or isolated islets liver (Michell et al. 1979, Eugenin et al. 1998), adrenocortico- (Oshikawa et al. 2004). While insulin secretion by AVP tropic hormone (ACTH) release from the anterior pituitary (Richardson et al. 1995, Oshikawa et al. 2004) and OT (Lee (Gillies et al. 1982, Rivier et al. 1984, Hernando et al. 2001), et al. 1995) has been shown to be induced via the V1b and water reabsorption in the kidney (Nielsen et al. 1995, receptor, previous studies with subtype-nonselective vaso- Ecelbarger et al. 2000). OT also plays crucial roles in uterine pressin receptor antagonists suggested that both the V1b and contraction (Fuchs et al. 1982, Goodwin et al. 1994) and milk the OT receptors were involved in glucagon secretion by ejection during lactation (Moos et al. 1989, Young et al. 1996). stimulation with AVP and OT (Yibchok-anun & Hsu 1998, In addition to these physiological roles, AVP and OT are Yibchok-anun et al. 1999). Although both V1b and OT known to regulate the circulating blood glucose level by receptors are involved in the glucagon secretion, no one has stimulating insulin and glucagon release (Dunning et al. 1984, analyzed this secretion when specific receptor is absent. Gao et al. 1990, 1991, 1992, Stock et al. 1990, Li et al. 1992, To elucidate the roles of the V1b receptor in glucagon Gao & Henquin 1993, Abu-Basha et al. 2002). secretion, we examined the mechanism of AVP- and AVP- and OT-induced pancreatic hormone secretion, OT-induced glucagon secretion using receptor-selective such as insulin and glucagon, is evoked by the activation of antagonists and V1b receptor knockout (V1bRK/K) mice AVP and OT receptors expressed in pancreatic islet cells. (Tanoue et al. 2004), in which tissue expression of the V1b Journal of Endocrinology (2007) 192, 361–369 DOI: 10.1677/joe.1.06864 0022–0795/07/0192–361 q 2007 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/30/2021 10:43:21PM via free access 362 Y FUJIWARA and others . AVP- and oxytocin-induced glucagon secretion receptor mRNA was undetectable (Oshikawa et al. 2004). First, water available ad libitum. All experiments followed the we examined whether SSR149415, a recently developed V1b institutional guidelines. receptor-specific antagonist (Serradeil-Le Gal et al. 2002, Folny et al. 2003, Oshikawa et al. 2004), inhibited AVP- and Isolation of pancreatic islets and glucagon measurement OT-induced glucagon secretion from primary cultured mouse islet cells. We next investigated the involvement of the OT Mouse pancreatic islets were isolated from male mice by receptor in AVP- and OT-induced glucagon secretion using collagenase digestion followed by Ficoll gradient separation 2; 4; 9 dðCH2Þ5½TyrðMeÞ Thr Tyr-NH2OVT (CL-14-26), an as described previously (Shibata et al. 1976, Oshikawa et al. OTreceptor-selective antagonist. Furthermore, we investigated 2004). Briefly, the mouse pancreas was injected with an glucagon secretion in V1bRK/K mice with the antagonists. aliquot of 3 ml Hanks’ medium containing 2 mg/ml We show here that both the V1b and the OT receptors collagenase S-1 through the choledoch duct by clamping fundamentally mediate AVP- and OT-induced glucagon one side of the duct to block the flow into the intestinal secretion respectively, and that signaling pathways through the tract. Pancreata were collected from four to five mice, and OT receptor can mediate and compensate AVP-induced incubated at 37 8C for 20 min. The reaction was stopped by glucagon secretion when the V1b receptor is completely the addition of ice-cold Hanks’ medium. The digested abolished. pancreata were washed with the same medium, filtrated through a Spectra-mesh (408 mm; Spectrum Laboratories, Inc., Ft. Lauderdale, FL, USA), and washed with the same medium. The samples were resuspended in 4 ml Ficoll Materials and Methods (specific gravity, 1.22) and then overlaid twice with 2 ml Ficoll with specific gravities of 1.09 and 1.05. After Materials centrifugation at 2000 g for 10 min, the islets were collected from the interface. The isolated islets were washed with an Fetal bovine serum (FBS) was from Thermo Trace RPMI 1640 medium containing 10% FBS, 11 mM glucose, (Melbourne, Australia). Hanks’ solution was from Nissui 50 U/ml penicillin, and 50 mg/ml streptomycin and pre- (Tokyo, Japan). AVP and OT were from the Peptide incubated for 2–3 h in the same medium at 37 8Cin5% 3 8 Institute (Osaka, Japan). [ H]AVP ([Arg ]-vasopressin, CO . Fifteen islets were used for one assay, and experiments 3 2 [phenylalanyl-3,4,5- H(N)]; specific activity, 60.0Ci/ including three or four assays in one dose were repeated four 3 3 mmol) and [ H]OT (OT, [tyrosyl-2,6- H]; specific to five times. After sampling of the baseline, AVP or OT activity, 48.0 Ci/mmol) were from Perkin–Elmer Life and stimulation was performed at 37 8C for 10 min. Arginine Analytical Sciences (Boston, MA, USA). SSR149415, (20 mM) was used as a positive control. Each antagonist was which was the specific antagonist for the V1b receptor, added 5 min before the stimulation with AVP or OT. was donated by Sanofi-Synthelabo (Montpelier, France). After stimulation, the supernatant was taken up and the 2; 4; 9 dðCH2Þ5½TyrðMeÞ Thr Tyr-NH2OVT (CL-14-26), glucagon concentration was measured using the glucagon which specifically antagonized the OT receptor (Elands ELISA kit. 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 Ligand binding assay dipropionate (DES) were purchased from Sigma-Aldrich Uterine tissues were isolated from female mice treated with (Tokyo, Japan). Collagenase S-1 was purchased from Nitta DES (0.3 mg/kg body weight) i.p., 20 h before isolation. (Osaka, Japan). Glucagon ELISA kits and all other Uterine cells stably expressing mouse V1b receptor were chemicals were purchased from WAKO (Tokyo, Japan). prepared as described previously (Oshikawa et al. 2004). Saturation binding studies were performed to incubate 20 mg Animals cell membrane and 50 mg uterine membrane preparations with various concentrations of [3H]AVP and [3H]OT (0.1– Male mice deficient in the V1b vasopressin receptor were 5.0 nM) in 250 ml assay buffer containing 50 mM Tris–HCl generated by gene targeting as described previously (Tanoue (pH 7.4), 10 mM MgCl2, and 0.05% BSA. For competition et al. 2004). Briefly, by homologous recombination, we binding studies, 1 nM [3H]AVP and 2 nM [3H]OT were disrupted exon 1, which contains the translation initiation added to cell membrane and uterine membrane preparations codon. The generated mutant mice were of a mixed genetic respectively, and incubated with various concentrations of background of 129Sv and C57BL/6.
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