5-IP7 is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis


Posted: 2021-10-19 19:00:00
. 2021 Oct 18. doi: 10.1038/s42255-021-00468-7. Online ahead of print. Xiaozhe Zhang # 1 , Na Li # 1 , Jun Zhang # 1 , Yanshen Zhang # 2 3 , Xiaoli Yang # 1 , Yifan Luo 1 , Bobo Zhang 1 , Zhixue Xu 1 , Zhenhua Zhu 1 , Xiuyan Yang 1 , Yuan Yan 1 , Biao Lin 1 , Shen Wang 4 , Da Chen 2 3 , Caichao Ye 5 , Yan Ding 6 , Mingliang Lou 6 , Qingcui Wu 6 , Zhanfeng Hou 6 , Keren Zhang 7 , Ziming Liang 8 , Anqi Wei 9 , Bianbian Wang 9 , Changhe Wang 9 , Nan Jiang 8 , Wenqing Zhang 5 , Guozhi Xiao 10 , Cong Ma 4 , Yan Ren 7 , Xiangbing Qi 6 , Weiping Han 11 12 , Chao Wang 13 14 , Feng Rao 15 Affiliations Expand Affiliations 1 School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. 2 Ministry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. 3 Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. 4 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. 5 Department of Physics and Shenzhen Institute for Quantum Science & Technology, Southern University of Science and Technology, Shenzhen, China. 6 National Institute of Biological Sciences, Beijing, China. 7 BGI-Shenzhen, Beishan Industrial Zone 11th building, Shenzhen, China. 8 Department of Hepatic Surgery, the Third People's Hospital of Shenzhen and the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China. 9 Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. 10 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, China. 11 Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore, Singapore. 12 Center for Neuro-Metabolism and Regeneration Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China. 13 Ministry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. cwangust@ustc.edu.cn. 14 Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. cwangust@ustc.edu.cn. 15 School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. raof@sustech.edu.cn. # Contributed equally. Item in Clipboard Xiaozhe Zhang et al. Nat Metab. 2021. Show details Display options Display options Format . 2021 Oct 18. doi: 10.1038/s42255-021-00468-7. Online ahead of print. Authors Xiaozhe Zhang # 1 , Na Li # 1 , Jun Zhang # 1 , Yanshen Zhang # 2 3 , Xiaoli Yang # 1 , Yifan Luo 1 , Bobo Zhang 1 , Zhixue Xu 1 , Zhenhua Zhu 1 , Xiuyan Yang 1 , Yuan Yan 1 , Biao Lin 1 , Shen Wang 4 , Da Chen 2 3 , Caichao Ye 5 , Yan Ding 6 , Mingliang Lou 6 , Qingcui Wu 6 , Zhanfeng Hou 6 , Keren Zhang 7 , Ziming Liang 8 , Anqi Wei 9 , Bianbian Wang 9 , Changhe Wang 9 , Nan Jiang 8 , Wenqing Zhang 5 , Guozhi Xiao 10 , Cong Ma 4 , Yan Ren 7 , Xiangbing Qi 6 , Weiping Han 11 12 , Chao Wang 13 14 , Feng Rao 15 Affiliations 1 School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. 2 Ministry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. 3 Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. 4 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. 5 Department of Physics and Shenzhen Institute for Quantum Science & Technology, Southern University of Science and Technology, Shenzhen, China. 6 National Institute of Biological Sciences, Beijing, China. 7 BGI-Shenzhen, Beishan Industrial Zone 11th building, Shenzhen, China. 8 Department of Hepatic Surgery, the Third People's Hospital of Shenzhen and the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China. 9 Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. 10 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, China. 11 Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore, Singapore. 12 Center for Neuro-Metabolism and Regeneration Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China. 13 Ministry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. cwangust@ustc.edu.cn. 14 Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. cwangust@ustc.edu.cn. 15 School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. raof@sustech.edu.cn. # Contributed equally. Item in Clipboard CiteDisplay options Display options Format Abstract 5-diphosphoinositol pentakisphosphate (5-IP7) is a signalling metabolite linked to various cellular processes. How extracellular stimuli elicit 5-IP7 signalling remains unclear. Here we show that 5-IP7 in β cells mediates parasympathetic stimulation of synaptotagmin-7 (Syt7)-dependent insulin release. Mechanistically, vagal stimulation and activation of muscarinic acetylcholine receptors triggers Gαq-PLC-PKC-PKD-dependent signalling and activates IP6K1, the 5-IP7 synthase. Whereas both 5-IP7 and its precursor IP6 compete with PIP2 for binding to Syt7, Ca2+ selectively binds 5-IP7 with high affinity, freeing Syt7 to enable fusion of insulin-containing vesicles with the cell membrane. β-cell-specific IP6K1 deletion diminishes insulin secretion and glucose clearance elicited by muscarinic stimulation, whereas mice carrying a phosphorylation-mimicking, hyperactive IP6K1 mutant display augmented insulin release, congenital hyperinsulinaemia and obesity. These phenotypes are absent in mice lacking Syt7. Our study proposes a new conceptual framework for inositol pyrophosphate physiology in which 5-IP7 acts as a GPCR second messenger at the interface between peripheral nervous system and metabolic organs, transmitting Gq-coupled GPCR stimulation to unclamp Syt7-dependent, and perhaps other, exocytotic events. © 2021. The Author(s), under exclusive licence to Springer Nature Limited. References Rosenbaum, D. M., Rasmussen, S. G. & Kobilka, B. K. The structure and function of G-protein-coupled receptors. Nature 459, 356–363 (2009). - PubMed - PMC - DOI Hatch, A. J. & York, J. D. SnapShot: inositol phosphates. Cell 143, 1030–1030 e1031 (2010). - PubMed - PMC - DOI Irvine, R. F. & Schell, M. J. Back in the water: the return of the inositol phosphates. Nat. Rev. Mol. Cell Biol. 2, 327–338 (2001). - PubMed - DOI - PMC Shears, S. B. Inositol pyrophosphates: why so many phosphates? Adv. Biol. Regul. 57, 203–216 (2015). - PubMed - DOI - PMC Wilson, M. S., Livermore, T. M. & Saiardi, A. Inositol pyrophosphates: between signalling and metabolism. Biochem. J. 452, 369–379 (2013). - PubMed - DOI - PMC Show all 85 references Grant support [x] Cite Copy Format: Send To [x]

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早期癌の腫瘍マーカーを安価で高感度に検出する新しい磁化ナノビーズをオーストラリアの研究チームが考案

グリフィス大学(オーストラリア)の研究者らは、癌の腫瘍マーカーを検出する新しい方法を開発し、早期診断に役立てようとしている。クイーンズランド・マイクロ・ナノテクノロジーセンターのムハマド・シディキー准教授と、グリフィス創薬研究所の細胞工場・バイオポリマーセンターのディレクターであるベルント・レーム教授が率いる研究チームは、新しいクラスの超常磁性ナノ材料を用いて、卵巣癌などの腫瘍マーカーを安価で高感度に検出する方法を考案した。 この研究成果は、2021年6月29日にACS Applied Materials and…

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