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Diabetologia
Published in: Diabetologia 2/2015

01-02-2015 | Article

Calcium influx activates adenylyl cyclase 8 for sustained insulin secretion in rat pancreatic beta cells

Authors: Haiqiang Dou, Changhe Wang, Xi Wu, Lijun Yao, Xiaoyu Zhang, Sasa Teng, Huadong Xu, Bin Liu, Qihui Wu, Quanfeng Zhang, Meiqin Hu, Yeshi Wang, Li Wang, Yi Wu, Shujiang Shang, Xinjiang Kang, Lianghong Zheng, Jin Zhang, Matthieu Raoux, Jochen Lang, Qing Li, Jing Su, Xiao Yu, Liangyi Chen, Zhuan Zhou

Published in: Diabetologia | Issue 2/2015

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Abstract

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.
Appendix
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Metadata
Title
Calcium influx activates adenylyl cyclase 8 for sustained insulin secretion in rat pancreatic beta cells
Authors
Haiqiang Dou
Changhe Wang
Xi Wu
Lijun Yao
Xiaoyu Zhang
Sasa Teng
Huadong Xu
Bin Liu
Qihui Wu
Quanfeng Zhang
Meiqin Hu
Yeshi Wang
Li Wang
Yi Wu
Shujiang Shang
Xinjiang Kang
Lianghong Zheng
Jin Zhang
Matthieu Raoux
Jochen Lang
Qing Li
Jing Su
Xiao Yu
Liangyi Chen
Zhuan Zhou
Publication date
01-02-2015
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 2/2015
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-014-3437-z

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