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Dive into the research topics where Yasuhito Uezono is active.

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Featured researches published by Yasuhito Uezono.


The Journal of Physiology | 1999

Evidence that multiple P2X purinoceptors are functionally expressed in rat supraoptic neurones

Izumi Shibuya; Keiko Tanaka; Yukio Hattori; Yasuhito Uezono; Nobuya Harayama; Jun Noguchi; Yoichi Ueta; Futoshi Izumi; Hiroshi Yamashita

1 The expression, distribution and function of P2X purinoceptors in the supraoptic nucleus (SON) were investigated by reverse transcription‐polymerase chain reaction (RT‐PCR), in situ hybridization, and Ca2+‐imaging and whole‐cell patch‐clamp techniques, respectively. 2 RT‐PCR analysis of all seven known P2X receptor mRNAs in circular punches of the SON revealed that mRNAs for P2X2, P2X3, P2X4, P2X6 and P2X7 receptors were expressed in the SON, and mRNAs for P2X3, P2X4 and P2X7 were predominant. 3 In situ hybridization histochemistry for P2X3 and P2X4 receptor mRNAs showed that both mRNAs were expressed throughout the SON and in the paraventricular nucleus (PVN). 4 ATP caused an increase in [Ca2+]i in a dose‐dependent manner with an ED50 of 1.7 × 10−5m. The effects of ATP were mimicked by ATPγS and 2‐methylthio ATP (2MeSATP), but not by AMP, adenosine, UTP or UDP. αβ‐Methylene ATP (αβMeATP) and ADP caused a small increase in [Ca2+]i in a subset of SON neurones. 5 The P2X7 agonist 2′‐ & 3′‐O‐(4‐benzoylbenzoyl)‐ATP (BzATP) at 10−4m increased [Ca2+]i, but the potency of BzATP was lower than that of ATP. In contrast, BzATP caused a more prominent [Ca2+]i increase than ATP in non‐neuronal cells in the SON. 6 The effects of ATP were abolished by extracellular Ca2+ removal or by the P2 antagonist pyridoxal phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS), and inhibited by extracellular Na+ replacement or another P2 antagonist, suramin, but were unaffected by the P2X7 antagonist oxidized ATP, and the inhibitor of Ca2+‐ATPase in intracellular Ca2+ stores cyclopiazonic acid. 7 Two patterns of desensitization were observed in the [Ca2+]i response to repeated applications of ATP: some neurones showed little or moderate desensitization, while others showed strong desensitization. 8 Whole‐cell patch‐clamp analysis showed that ATP induced cationic currents with marked inward rectification. The ATP‐induced currents exhibited two patterns of desensitization similar to those observed in the [Ca2+]i response. 9 The results suggest that multiple P2X receptors, including P2X3, are functionally expressed in SON neurones, and that activation of these receptors induces cationic currents and Ca2+ entry. Such ionic and Ca2+‐signalling mechanisms triggered by ATP may play an important role in the regulation of SON neurosecretory cells.


Translational Psychiatry | 2011

Potentiation of ghrelin signaling attenuates cancer anorexia – cachexia and prolongs survival

Naoki Fujitsuka; Akihiro Asakawa; Yasuhito Uezono; Kouichiro Minami; Takuhiro Yamaguchi; A Niijima; T Yada; Y Maejima; U Sedbazar; Takafumi Sakai; T Hattori; Yoshio Kase; Akio Inui

Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia.


Journal of Neurochemistry | 2002

Pituitary Adenylate Cyclase‐Activating Polypeptide Causes Ca2+ Release from Ryanodine/Caffeine Stores Through a Novel Pathway Independent of Both Inositol Trisphosphates and Cyclic AMP in Bovine Adrenal Medullary Cells

Keiko Tanaka; Izumi Shibuya; Yasuhito Uezono; Yoichi Ueta; Yumiko Toyohira; Nobuyuki Yanagihara; Futoshi Izumi; Tomio Kanno; Hiroshi Yamashita

Abstract: Pituitary adenylate cyclase‐activating polypeptide (PACAP) causes both Ca2+ release and Ca2+ influx in bovine adrenal chromaffin cells. To elucidate the mechanisms of PACAP‐induced Ca2+ release, we investigated expression of PACAP receptors and measured inositol trisphosphates (IP3), cyclic AMP, and the intracellular Ca2+ concentration in bovine adrenal medullary cells maintained in primary culture. RT‐PCR analysis revealed that bovine adrenal medullary cells express the PACAP receptor hop, which is known to couple with both IP3 and cyclic AMP pathways. The two naturally occurring forms of PACAP, PACAP38 and PACAP27, both increased cyclic AMP and IP3, and PACAP38 was more potent than PACAP27 in both effects. Despite the effects of PACAP on IP3 production, the Ca2+ release induced by PACAP38 or by PACAP27 was unaffected by cinnarizine, a blocker of IP3 channels. The potencies of the peptides to cause Ca2+ release in the presence of cinnarizine were similar. The Ca2+ release induced by PACAP38 or by PACAP27 was strongly inhibited by ryanodine and caffeine. In the presence of ryanodine and caffeine, PACAP38 was more potent than PACAP27. PACAP‐induced Ca2+ release was unaffected by Rp‐adenosine 3′,5′‐cyclic monophosphothioate, an inhibitor of protein kinase A. Ca2+ release induced by bradykinin and angiotensin II was also inhibited by ryanodine and caffeine, but unaffected by cinnarizine. Although IP3 production stimulated by PACAP38 or bradykinin was abolished by the phospholipase C inhibitor, U‐73122, Ca2+ release in response to the peptides was unaffected by U‐73122. These results suggest that PACAP induces Ca2+ release from ryanodine/caffeine stores through a novel intracellular mechanism independent of both IP3 and cyclic AMP and that the mechanism may be the common pathway through which peptides release Ca2+ in adrenal chromaffin cells.


Neuroscience Letters | 2001

Aquaporin subtypes in rat cerebral microvessels

Hideyuki Kobayashi; Shin-ichi Minami; Satoru Itoh; Seiji Shiraishi; Hiroki Yokoo; Toshihiko Yanagita; Yasuhito Uezono; Motohiko Mohri; Akihiko Wada

We investigated the expression of aquaporin (AQP) subtypes in the rat cerebral microvessels by reverse transcription-polymerase chain reaction, immunoblotting and immunohistochemistry. mRNA for AQP4, but not for AQP1, 2, 3 or 5, was detected in the microvessels. Immunoblot analysis showed that AQP4 protein was detected as a 30 kDa band with higher molecular weight bands. Immunohistochemical staining showed that AQP4 was located on cell surface of the cerebral microvessels. These results suggest that AQP4 in the cerebral microvessels is involved in the regulation of water transport between blood and brain.


European Journal of Pharmacology | 1996

Adrenomedullin-sensitive receptors are preferentially expressed in cultured rat mesangial cells

Akihiko Osajima; Yasuhito Uezono; Masahito Tamura; Kazuo Kitamura; Yoshinobu Mutoh; Yoichi Ueta; Kenji Kangawa; Masaru Kawamura; Tanenao Eto; Hiroshi Yamashita; Futoshi Izumi; Masayuki Takasugi; Akio Kuroiwa

By using cultured rat mesangial cells, we compared the effects on cyclic nucleotide levels of adrenomedullin with those of the structurally related peptides, calcitonin gene-related peptide (CGRP) and amylin. Adrenomedullin potently increased cAMP levels 7-fold in a time- and concentration-dependent manner. Its EC50 was 3 x 10(-9) M. CGRP was less potent (2-fold) with an EC50 of 10(-7) M, and amylin had no effect on cAMP levels. All three peptides failed to increase cGMP levels. Treatment of cells with near maximal concentrations of adrenomedullin (10(-7) M) and CGRP (10(-6) M) had no additive effect on cAMP levels. Human adrenomedullin-(22-52)-NH2, a putative adrenomedullin receptor antagonist, inhibited the production of cAMP elicited by adrenomedullin (IC50: 7 x 10(-8) M) and CGRP (IC50: 5 x 10(-8) M). Human CGRP-(8-37), a CGRP receptor antagonist, conversely, reduced the cAMP elevation caused by these peptides with a lower potency (IC50: 10(-6) M for both peptides). This demonstrated that human adrenomedullin-(22-52)-NH2 was a more effective antagonist for adrenomedullin- and CGRP-specific receptors than human CGRP-(8-37). Results suggest that receptors sensitive to adrenomedullin are preferentially expressed in cultured rat mesangial cells. Immunohistochemical study showed almost no immunoreactive adrenomedullin and CGRP, if any, in the cells. Adrenomedullin may regulate mesangial function as either a paracrine or circulating hormone via a cAMP- but not a cGMP-dependent mechanism.


Anesthesia & Analgesia | 2002

The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors.

Yousuke Shiga; Kouichiro Minami; Munehiro Shiraishi; Yasuhito Uezono; Osamu Murasaki; Muneshige Kaibara; Akio Shigematsu

Tramadol is a widely used analgesic, but its mechanism of action is not completely understood. Muscarinic receptors are involved in neuronal function in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets of analgesic drugs in the central nervous system. In this study, we investigated the effects of tramadol on type-3 muscarinic (M3) receptors using the Xenopus oocyte expression system. Tramadol (10 nM–100 &mgr;M) inhibited acetylcholine-induced currents in oocytes expressing M3 receptor. Although GF109203X, a protein kinase C inhibitor, increased the basal current, it had little effect on the inhibition of acetylcholine-induced currents by tramadol. Moreover, tramadol inhibited the specific binding sites of [3H]quinuclidinyl benzilate. These findings suggest that tramadol at clinically relevant concentrations inhibits M3 function via quinuclidinyl benzilate-binding sites. This may explain the modulation of neuronal function and the anticholinergic effects of tramadol.


British Journal of Pharmacology | 2000

Adrenomedullin inhibits spontaneous and bradykinin‐induced but not oxytocin‐ or prostaglandin F2α‐induced periodic contraction of rat uterus

Toshihiko Yanagita; Ryuichi Yamamoto; Takashi Sugano; Hideyuki Kobayashi; Yasuhito Uezono; Hiroki Yokoo; Seiji Shiraishi; Shin-ichi Minami; Akihiko Wada

In isolated rat uterine strips, adrenomedullin (AM) inhibited the spontaneous periodic contraction in a concentration‐dependent manner (IC50=22.3±0.7 nM). The inhibitory effect of AM was prevented by either AM22–52, a putative antagonist for AM receptors, or calcitonin gene‐related peptide (CGRP)8–37, a putative antagonist for CGRP receptors. AM also attenuated bradykinin (BK)‐induced periodic uterine contraction, which was blocked by AM22–52 or CGRP8–37, whereas AM had no effect on the periodic contraction caused by oxytocin or prostaglandin F2α (PGF2α). RT–PCR analysis showed that mRNAs for calcitonin receptor‐like receptor (CRLR), receptor‐activity‐modifying protein (RAMP)1, RAMP2 and RAMP3 were expressed in the rat uterus. These results demonstrate that AM selectively inhibits spontaneous and BK‐induced periodic contraction via activating receptors for AM and CGRP.


Neurochemistry International | 2010

Activation of the neurokinin-1 receptor in rat spinal astrocytes induces Ca2+ release from IP3-sensitive Ca2+ stores and extracellular Ca2+ influx through TRPC3

Kanako Miyano; Norimitsu Morioka; Tatsuhiko Sugimoto; Seiji Shiraishi; Yasuhito Uezono; Yoshihiro Nakata

Substance P (SP) plays an important role in pain transmission through the stimulation of the neurokinin (NK) receptors expressed in neurons of the spinal cord, and the subsequent increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) as a result of this stimulation. Recent studies suggest that spinal astrocytes also contribute to SP-related pain transmission through the activation of NK receptors. However, the mechanisms involved in the SP-stimulated [Ca(2+)](i) increase by spinal astrocytes are unclear. We therefore examined whether (and how) the activation of NK receptors evoked increase in [Ca(2+)](i) in rat cultured spinal astrocytes using a Ca(2+) imaging assay. Both SP and GR73632 (a selective agonist of the NK1 receptor) induced both transient and sustained increases in [Ca(2+)](i) in a dose-dependent manner. The SP-induced increase in [Ca(2+)](i) was significantly attenuated by CP-96345 (an NK1 receptor antagonist). The GR73632-induced increase in [Ca(2+)](i) was completely inhibited by pretreatment with U73122 (a phospholipase C inhibitor) or xestospongin C (an inositol 1,4,5-triphosphate (IP(3)) receptor inhibitor). In the absence of extracellular Ca(2+), GR73632 induced only a transient increase in [Ca(2+)](i). In addition, H89, an inhibitor of protein kinase A (PKA), decreased the GR73632-mediated Ca(2+) release from intracellular Ca(2+) stores, while bisindolylmaleimide I, an inhibitor of protein kinase C (PKC), enhanced the GR73632-induced influx of extracellular Ca(2+). RT-PCR assays revealed that canonical transient receptor potential (TRPC) 1, 2, 3, 4 and 6 mRNA were expressed in spinal astrocytes. Moreover, BTP2 (a general TRPC channel inhibitor) or Pyr3 (a TRPC3 inhibitor) markedly blocked the GR73632-induced sustained increase in [Ca(2+)](i). These findings suggest that the stimulation of the NK-1 receptor in spinal astrocytes induces Ca(2+) release from IP(3-)sensitive intracellular Ca(2+) stores, which is positively modulated by PKA, and subsequent Ca(2+) influx through TRPC3, which is negatively regulated by PKC.


Psychopharmacology | 2000

Inhibitory effects of clozapine and other antipsychotic drugs on noradrenaline transporter in cultured bovine adrenal medullary cells

Reiji Yoshimura; Nobuyuki Yanagihara; Koji Hara; Takeshi Terao; Jun Nakamura; Susumu Ueno; Yumiko Toyohira; Yasuhito Uezono; S. Kaneko; Masaru Kawamura; Kazuhiko Abe; Futoshi Izumi

Abstract The effects of clozapine and other antipsychotic drugs on noradrenaline (NA) transport were examined in cultured bovine adrenal medullary cells and in transfected Xenopus laevis oocytes expressing the bovine NA transporter. Incubation of adrenal medullary cells with clozapine (30–1000 ng/ml) inhibited desipramine (DMI)-sensitive uptake of [3H]NA in a concentration-dependent manner (IC50=110 ng/ml or 336 nM). Other antipsychotic drugs such as haloperidol, chlorpromazine, and risperidone also decreased [3H]NA uptake (IC50= 144, 220, and 210 ng/ml or 383, 690, and 512 nM, respectively). Eadie-Hofstee analysis showed that clozapine reduced Vmax of uptake of [3H]NA and increased Km. Furthermore, clozapine inhibited specific binding of [3H]DMI to plasma membranes isolated from bovine adrenal medulla (IC50=48 ng/ml or 146 nM). Scatchard plot analysis of [3H]DMI binding revealed that clozapine decreased both Bmax and Kd. Other antipsychotic drugs, including haloperidol, chlorpromazine, and risperidone, also reduced [3H]DMI binding to the membranes. In transfected Xenopus oocytes expressing the bovine NA transporter, clozapine inhibited [3H]NA uptake in a concentration-dependent manner similar to that observed in adrenal medullary cells. These results suggest that clozapine and haloperidol directly inhibit transport of NA by acting on the site of an NA transporter that influences both substrate transport and binding of tricyclic antidepressants.


Molecular Brain Research | 2000

Adrenomedullin receptors in rat cerebral microvessels.

Hideyuki Kobayashi; Shin-ichi Minami; Ryuichi Yamamoto; Keizo Masumoto; Toshihiko Yanagita; Yasuhito Uezono; Kimiyuki Tsuchiya; Motohiko Mohri; Kazuo Kitamura; Tanenao Eto; Akihiko Wada

To characterize the sites of action of adrenomedullin (AM) in the cerebral microvasculature, we studied the effect of AM on cyclic AMP (cAMP) level as well as expression of AM and its receptor in the rat cerebral microvessels. The microvessels were prepared from rat cerebral cortex by albumin flotation and glass bead filtration technique. AM and calcitonin gene-related peptide (CGRP) increased cAMP level in the microvessels in a concentration-dependent manner. The effect of AM was more than 100 times more potent than that of CGRP. The accumulation of cAMP by AM was inhibited by AM[22-52], an AM receptor antagonist, but not by CGRP[8-37], a CGRP receptor antagonist, suggesting that AM increased cAMP accumulation by acting on receptors specific to AM. [125I]AM binding to the microvessels was displaced by AM and less potently by AM[22-52]. The displacing potencies of CGRP and CGRP[8-37] were very weak. mRNAs for AM as well as calcitonin-receptor-like receptor and receptor-activity-modifying protein 2 which form a receptor specific to AM, were highly expressed in the microvessels. These results provide biochemical and pharmacological evidence that AM is produced in and acts on the cerebral microvessels in an autocrine/paracrine manner and is involved in regulation of cerebral microcirculation.

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Nobuyuki Yanagihara

University of Occupational and Environmental Health Japan

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Yuka Sudo

Tokyo University of Science

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Munehiro Shiraishi

University of Occupational and Environmental Health Japan

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