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Hv1 channel supports insulin secretion in pancreatic β cells through calcium entry, depolarization and intracellular pH regulation

Huimin Pang, Xudong Wang, Wang Xi, Qing Zhao, Shangrong Zhang, Jiwei Qin, Jili Lv, Yongzhe Che, Weiyan Zuo, Shu Jie Li
doi: https://doi.org/10.1101/097816
Huimin Pang
aDepartment of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, P. R. China
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Xudong Wang
aDepartment of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, P. R. China
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Wang Xi
aDepartment of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, P. R. China
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Qing Zhao
aDepartment of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, P. R. China
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Shangrong Zhang
aDepartment of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, P. R. China
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Jiwei Qin
aDepartment of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, P. R. China
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Jili Lv
aDepartment of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, P. R. China
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Yongzhe Che
bSchool of Medicine, Nankai University, Tianjin 300071, P. R. China
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Weiyan Zuo
aDepartment of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, P. R. China
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Shu Jie Li
aDepartment of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, P. R. China
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  • For correspondence: shujieli@nankai.edu.cn
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Abstract

Here, we demonstrate that the voltage-gated proton channel Hv1 represents a regulatory mechanism for insulin secretion of pancreatic islet β cell. In vivo, Hv1-deficient mice display hyperglycemia and glucose intolerance due to reduced insulin secretion, but normal peripheral insulin sensitivity. In vitro, islets of Hv1-deficient and heterozygous mice, INS-1 (832/13) cells with siRNA-mediated knockdown of Hv1 exhibit a marked defect in glucose- and K+-induced insulin secretion. Hv1 deficiency decreases both insulin and proinsulin contents, and limits glucose-induced Ca2+ entry and membrane depolarization. Furthermore, loss of Hv1 increases insulin-containing granular pH and decreases cytosolic pH. In addition, histologic studies show a decrease in β cell mass in islets of Hv1-deficient mice. Collectively, our results indicate that Hv1 supports insulin secretion in the β cell by calcium entry, membrane depolarization and intracellular pH regulation.

SIGNIFICANCE STATEMENT The voltage-gated proton channel Hv1 is highly expressed in insulin-containing granules in pancreatic β cells. Hv1 supports insulin secretion in the β cell by calcium entry, membrane depolarization and regulation of intragranular and cytosolic pH, which represents a regulatory mechanism for insulin secretion of pancreatic islet β cell. Our research demonstrates that Hv1 expressed in β cell is required for insulin secretion and maintains glucose homeostasis, and reveals a significant role for the proton channel in the modulation of pancreatic β cell function.

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Posted September 05, 2018.
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Hv1 channel supports insulin secretion in pancreatic β cells through calcium entry, depolarization and intracellular pH regulation
Huimin Pang, Xudong Wang, Wang Xi, Qing Zhao, Shangrong Zhang, Jiwei Qin, Jili Lv, Yongzhe Che, Weiyan Zuo, Shu Jie Li
bioRxiv 097816; doi: https://doi.org/10.1101/097816
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Hv1 channel supports insulin secretion in pancreatic β cells through calcium entry, depolarization and intracellular pH regulation
Huimin Pang, Xudong Wang, Wang Xi, Qing Zhao, Shangrong Zhang, Jiwei Qin, Jili Lv, Yongzhe Che, Weiyan Zuo, Shu Jie Li
bioRxiv 097816; doi: https://doi.org/10.1101/097816

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