G-protein-coupled receptor 40 agonist GW9508 potentiates glucose-stimulated insulin secretion through activation of protein kinase Cα and ε in INS-1 cells
Autoři:
Takuya Hashimoto aff001; Hideo Mogami aff002; Daisuke Tsuriya aff001; Hiroshi Morita aff001; Shigekazu Sasaki aff001; Tatsuro Kumada aff003; Yuko Suzuki aff004; Tetsumei Urano aff004; Yutaka Oki aff001; Takafumi Suda aff001
Působiště autorů:
2nd Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
aff001; Department of Health and Nutrition, Tokoha University, Shizuoka, Japan
aff002; Department of Occupational Therapy, Tokoha University, Shizuoka, Japan
aff003; Department of Medical Physiology, Hamamatsu University School of Medicine, Shizuoka, Japan
aff004; Department of Family and Community Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
aff005
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0222179
Souhrn
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 (3 mM and 20 mM) 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 3 mM and 20 mM 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 3 mM glucose, GW9508 induced sustained MARCKS-GFP translocation to the cytosol, irrespective of changes in [Ca2+]i. At 20 mM 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 3 mM glucose. At 20 mM glucose, GW9508 induced transient translocation of PKCα and sustained translocation as well as transient translocation of PKCε. While the inhibitors (75 μM) 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.
Klíčová slova:
Physical sciences – Chemistry – Chemical compounds – Organic compounds – Carbohydrates – Monosaccharides – Glucose – Organic chemistry – Medicine and health sciences – Endocrinology – Endocrine physiology – Insulin secretion – Diabetic endocrinology – Insulin – Biology and life sciences – Physiology – Cell biology – Signal transduction – Cell signaling – Glucose signaling – Cytosol – Cellular structures and organelles – Cell membranes – Biochemistry – Hormones – Research and analysis methods – Microscopy – Light microscopy – Fluorescence microscopy – Imaging techniques – Fluorescence imaging
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PLOS One
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