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

著者

    • Shahid, Mohammad

書誌事項

タイトル

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

タイトル別名

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

著者名

Shahid, Mohammad

学位授与大学

富山大学

取得学位

博士(理学)

学位授与番号

甲第52号

学位授与年月日

2013-09-27

注記・抄録

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

開始ページ : 1

終了ページ : 37

NII論文ID : http://ci.nii.ac.jp/naid/500000731217

目次

  1. 2016-04-01 再収集 / (index.pdf)
  2. 2016-04-01 再収集 / (index_1.pdf)
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各種コード

  • NII論文ID(NAID)
    500000731217
  • NII著者ID(NRID)
    • 8000000881802
  • DOI(JaLC)
  • DOI
  • 本文言語コード
    • eng
  • データ提供元
    • 機関リポジトリ
    • NDLデジタルコレクション
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