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Calcium influx activates adenylyl cyclase 8 for sustained insulin secretion in rat pancreatic beta cells
- 作者:Haiqiang Dou (1) (2) (3) (4) (5)
Changhe Wang (1) (2) (3) (4) (5) Xi Wu (1) (2) (3) (4) (5) Lijun Yao (1) (2) (3) (4) (5) Xiaoyu Zhang (1) (2) (3) (4) (5) Sasa Teng (1) (2) (3) (4) (5) Huadong Xu (1) (2) (3) (4) (5) Bin Liu (1) (2) (3) (4) (5) Qihui Wu (1) (2) (3) (4) (5) Quanfeng Zhang (1) (2) (3) (4) (5) Meiqin Hu (1) (2) (3) (4) (5) Yeshi Wang (1) (2) (3) (4) (5) Li Wang (1) (2) (3) (4) (5) Yi Wu (1) (3) Shujiang Shang (1) (2) (3) (4) (5) Xinjiang Kang (1) (2) (3) (4) (5) Lianghong Zheng (1) (2) (3) (4) (5) Jin Zhang (6) Matthieu Raoux (7) Jochen Lang (7) Qing Li (8) Jing Su (8) Xiao Yu (8) Liangyi Chen (1) (3) Zhuan Zhou (1) (2) (3) (4) (5)
1. Institute of Molecular Medicine ; Peking University ; 5 Yiheyuan Road ; Beijing ; 100871 ; China 2. State Key Laboratory of Biomembrane and Membrane Biotechnology ; Peking University ; Beijing ; People鈥檚 Republic of China 3. Beijing Key Laboratory of Cardiometabolic Molecular Medicine ; Peking University ; Beijing ; People鈥檚 Republic of China 4. PKU-IDG/McGovern Institute for Brain Research ; Peking University ; Beijing ; People鈥檚 Republic of China 5. Peking-Tsinghua Centre for Life Sciences ; Peking University ; Beijing ; People鈥檚 Republic of China 6. Department of Pharmacology and Molecular Sciences ; The Johns Hopkins University School of Medicine ; Baltimore ; MD ; USA 7. Universit茅 de Bordeaux I Institut Europ茅en de Chimie et Biologie UMR CNRS 5248 ; Bordeaux ; France 8. Department of Physiology ; Shandong University School of Medicine ; 44 Wenhua Xi Road ; Jinan ; 250012 ; People鈥檚 Republic of China
- 关键词:Adenylyl cyclase 8 ; Ca2+ ; Pancreatic beta cell ; Protein kinase A ; Vesicle pool
- 刊名:Diabetologia
- 出版年:2015
- 出版时间:February 2015
- 年:2015
- 卷:58
- 期:2
- 页码:324-333
- 全文大小:1,309 KB
- 参考文献:1. Tarasov AI, Semplici F, Ravier MA et al (2012) The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic beta-cells. Plos One 7:e39722
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- 刊物类别:Medicine
- 刊物主题:Medicine & Public Health
Internal Medicine Metabolic Diseases Human Physiology
- 出版者:Springer Berlin / Heidelberg
- ISSN:1432-0428
文摘
Aims/hypothesis Insulin is a key metabolic regulator in health and diabetes. In pancreatic beta cells, insulin release is regulated by the major second messengers Ca2+ and cAMP: exocytosis is triggered by Ca2+ and mediated by the cAMP/protein kinase A (PKA) signalling pathway. However, the causal link between these two processes in primary beta cells remains undefined. Methods Time-resolved confocal imaging of fluorescence resonance energy transfer signals was performed to visualise PKA activity, and combined membrane capacitance recordings were used to monitor insulin secretion from patch-clamped rat beta cells. Results Membrane depolarisation-induced Ca2+ influx caused an increase in cytosolic PKA activity via activating a Ca2+-sensitive adenylyl cyclase 8 (ADCY8) subpool. Glucose stimulation triggered coupled Ca2+ oscillations and PKA activation. ADCY8 knockdown significantly reduced the level of depolarisation-evoked PKA activation and impaired replenishment of the readily releasable vesicle pool. Pharmacological inhibition of PKA by two inhibitors reduced depolarisation-induced PKA activation to a similar extent and reduced the capacity for sustained vesicle exocytosis and insulin release. Conclusions/interpretation Our findings suggest that depolarisation-induced Ca2+ influx plays dual roles in regulating exocytosis in rat pancreatic beta cells by triggering vesicle fusion and replenishing the vesicle pool to support sustained insulin release. Therefore, Ca2+ influx may be important for glucose-stimulated insulin secretion.
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