Functional compensation among metabotropic receptors involved in cytosolic Ca^<2+> signaling and satiety control mechanisms

• 資料種別: 博士論文
• タイトル: Functional compensation among metabotropic receptors involved in cytosolic Ca^<2+> signaling and satiety control mechanisms
• 著者・編者: Shahid, Mohammad
• 出版年月日等: 2013-09-27
• 出版年（W3CDTF）: 2013-09-27
• 並列タイトル等: 満腹制御や細胞質Ca^<2+>シグナリングに関する代謝型受容体の機能的補償現象
• 授与機関名: 富山大学
• 授与年月日: 2013-09-27
• 授与年月日（W3CDTF）: 2013-09-27
• 報告番号: 甲第52号
• 学位: 博士（理学）
• 博論授与番号: 甲第52号
• 本文の言語コード: eng
• 一般注記: The peptide cholecystokinin (CCK) originally described as a gut hormone secreted from duodenum (intestine) is a ubiquitous neuropeptide involved in a variety of homeostatic and physiological functions. A product of obese (Ob) gene leptin is circulating protein synthesized by the white adipose tissue. Both of these are functioning as signaling messengers involved in regulation of food intake and energy homeostasis, whereas their receptor localization, physiological interaction and functional compensation between receptors / or its receptor subtypes in the hypothalamic satiety centers are not well characterized. In the present study, we examined fura-2 based intracellular Ca^<2+> imaging in acutely isolated mouse hypothalamic slices to analyze leptin and CCK-mediated signaling in details using gene knockout mice lacking CCK-1 receptors (CCK1R-/-). The CCK receptors are categorized into two subtypes, CCK-1 and -2, both of which share a common phosphatidylinositol signaling pathway to mobilize intracellular Ca^<2+> following receptor stimulations. We focused CCK-mediated Ca^<2+> signaling in parvocellular paraventricular nucleus (PVN) cells, which control satiety and represent highest expression of CCK-1 receptors in the brain. Analysis of mouse hypothalamic slices demonstrated that the general CCK receptor agonist CCK-8s (10 nM) triggered Ca^<2+> transients most significantly in the posterior sub-region of the PVN (PaPo). This 10 nM CCK-8s-induced response was absent in CCK1R-/- slices, showing that the response is mediated by CCK-1 receptors. CCK-8s concentrations higher than 30 nM triggered a Ca^<2+> rise similarly in wild-type and CCK1R-/- slices. The large CCK-8s (100 nM)-induced Ca^<2+> responses in CCK1R-/- slices were blocked by a CCK-2 receptor antagonist (CI-988), whereas those in wild-type slices required a mixture of CI-988 and lorglumide (a CCK-1 receptor antagonist) for complete antagonism. Therefore, CCK-1 and -2 receptors may function synergistically in single PaPo neurons and deletion of CCK-1 receptors may facilitate CCK-2 receptor signaling. This hypothesis was supported by results of real-time RT-PCR, immunofluorescence double labeling and western blotting assays, which indicated CCK-2 receptor over expression in PaPo neurons of CCK1R-/- mice. Furthermore, behavioral studies showed that intraperitoneal injections of lorglumide up-regulated food accesses in wild-type but not in CCK1R -/- mice, whereas CI-988 injections up-regulated food accesses in CCK1R-/- but not in wild-type mice. The compensatory CCK receptor signaling shed light on currently controversial satiety-controlling mechanisms in CCK1R-/- mice. Because of regular food intake activities and body weights are also reported for CCK null mutant mice, functional compensation for molecules underlying CCK-mediated satiety controls may not be limited to the two CCK receptor subtypes, and may also include other receptor signaling molecules such as leptin. So, we further extended our study focused on leptin and CCK signaling in hypothalamic neurons. Our preliminary data based on Ca2+ imaging and real time RT-PCR assay indicated that leptin and CCK-1 receptor signaling were synergistically interacted in PVN neurons as in the case of CCK-1 and -2 receptors. These results suggested receptor-wide as well as subtype-wide compensatory mechanisms in the regulation of satiety via metabotropic receptors.; 富山大学・富生命博甲第52号・Shahid Mohammad・2013/09/27; NII論文ID : 500000731217; 開始ページ : 1; 終了ページ : 37
• DOI: info:doi/10.15099/00005018; https://doi.org/info:doi/10.15099/00005018
• 国立国会図書館永続的識別子: info:ndljp/pid/8949143; https://dl.ndl.go.jp/pid/8949143
• コレクション（共通）: 障害者向け資料
• コレクション（障害者向け資料：レベル1）: テキストデータ
• コレクション（個別）: 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• 収集根拠: 博士論文（自動収集）
• 公開開始日（W3CDTF）: 2015-03-03
• 受理日（W3CDTF）: 2015-02-03T05:25:05+09:00
• 作成日（W3CDTF）: 2016-02-17
• 記録形式（IMT）: PDF
• オンライン閲覧公開範囲: 国立国会図書館内限定公開
• デジタル化資料送信: 図書館・個人送信対象外
• 遠隔複写可否（NDL）: 可
• 掲載誌（URI）: http://hdl.handle.net/10110/12560
• 連携機関・データベース: 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp

目次

2016-04-01 再収集

2016-04-01 再収集