G-protein-coupled receptor 40 agonist GW9508 potentiates glucose-stimulated insulin secretion through activation of protein kinase Cα and ε in INS-1 cells

橋本, 卓也

doi:https://doi.org/10.1371/journal.pone.0222179

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G-protein-coupled receptor 40 agonist GW9508 potentiates glucose-stimulated insulin secretion through activation of protein kinase Cα and ε in INS-1 cells

http://hdl.handle.net/10271/00003719

名前 / ファイル	ライセンス	アクション
論文本文 (1.7 MB)

Item type

学位論文 / Thesis or Dissertation(1)

公開日

2020-04-28

タイトル

G-protein-coupled receptor 40 agonist GW9508 potentiates glucose-stimulated insulin secretion through activation of protein kinase Cα and ε in INS-1 cells

言語

eng

資源タイプ

資源タイプ識別子

http://purl.org/coar/resource_type/c_db06

資源タイプ

doctoral thesis

アクセス権

open access

アクセス権URI

http://purl.org/coar/access_right/c_abf2

その他のタイトル

Gタンパク質共益型受容体40作動薬であるGW9508はINS-1細胞においてプロテインキナーゼ Cα および ε の活性化を介してグルコース刺激性インスリン分泌を増強する

著者

橋本, 卓也

書誌情報

en : PloS one

巻 14, 号 9, p. e0222179, 発行日 2019-09-09

出版者

PLoS (Public Library of Science)

言語

抄録

内容記述タイプ

Abstract

内容記述

Objective: The mechanism by which G-protein-coupled receptor 40 (GPR40) signaling amplifies glucose-stimulated insulin secretion through activation of protein kinase C (PKC) is unknown. We examined whether a GPR40 agonist, GW9508, could stimulate conventional and novel isoforms of PKC at two glucose concentrations (3mM and 20mM) in INS-1D cells.
Methods: Using epifluorescence microscopy, we monitored relative changes in the cytosolic fluorescence intensity of Fura2 as a marker of change in intracellular Ca2+([Ca2+]i) and relative increases in green fluorescent protein (GFP)-tagged myristoylated alanine-rich C kinase substrate (MARCKS-GFP) as a marker of PKC activation in response to GW9508 at 3mM and 20mM glucose. To assess the activation of the two PKC isoforms, relative increases in membrane fluorescence intensity of PKCα-GFP and PKCε-GFP were measured by total internal reflection fluorescence microscopy. Specific inhibitors of each PKC isotype were constructed and synthesized as peptide fusions with the third α-helix of the homeodomain of Antennapedia.
Results: At 3mM glucose, GW9508 induced sustained MARCKS-GFP translocation to the cytosol, irrespective of changes in [Ca2+]i. At 20mM glucose, GW9508 induced sustained MARCKS-GFP translocation but also transient translocation that followed sharp increases in [Ca2+]i. Although PKCα translocation was rarely observed, PKCε translocation to the plasma membrane was sustained by GW9508 at 3mM glucose. At 20mM glucose, GW9508 induced transient translocation of PKCα and sustained translocation as well as transient translocation of PKCε. While the inhibitors (75μM) of each PKC isotype reduced GW9508-potentiated, glucose-stimulated insulin secretion in INS-1D cells, the PKCε inhibitor had a more potent effect.
Conclusion: GW9508 activated PKCε but not PKCα at a substimulatory concentration of glucose. Both PKC isotypes were activated at a stimulatory concentration of glucose and contributed to glucose-stimulated insulin secretion in insulin-producing cells.

言語

学位名

博士（医学）

学位の区分

内容記述

doctoral

学位の分野

内容記述

医学系研究科

学位授与機関

学位授与機関識別子Scheme

kakenhi

学位授与機関識別子

13802

学位授与機関名

浜松医科大学

学位授与年月日

2020-02-13

学位授与番号

甲第822号

EISSN

収録物識別子タイプ

EISSN

収録物識別子

1932-6203

PubMed番号

識別子タイプ

PMID

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2023-06-20 16:35:24.169773

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G-protein-coupled receptor 40 agonist GW9508 potentiates glucose-stimulated insulin secretion through activation of protein kinase Cα and ε in INS-1 cells

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