CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes

Abstract Hepatic glucose production by glucagon is crucial for glucose homeostasis during fasting, yet the underlying mechanisms remain incompletely delineated. Although CD38 has been detected in the nucleus, its function in this compartment is unknown. Here, we demonstrate that nuclear CD38 (nCD38)...

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Main Authors: So-Young Rah, Yeonsoo Joe, Jeongmin Park, Stefan W. Ryter, Chansu Park, Hun Taeg Chung, Uh-Hyun Kim
Format: Article
Language:English
Published: Nature Publishing Group 2023-07-01
Series:Experimental and Molecular Medicine
Online Access:https://doi.org/10.1038/s12276-023-01034-9
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author So-Young Rah
Yeonsoo Joe
Jeongmin Park
Stefan W. Ryter
Chansu Park
Hun Taeg Chung
Uh-Hyun Kim
author_facet So-Young Rah
Yeonsoo Joe
Jeongmin Park
Stefan W. Ryter
Chansu Park
Hun Taeg Chung
Uh-Hyun Kim
author_sort So-Young Rah
collection DOAJ
description Abstract Hepatic glucose production by glucagon is crucial for glucose homeostasis during fasting, yet the underlying mechanisms remain incompletely delineated. Although CD38 has been detected in the nucleus, its function in this compartment is unknown. Here, we demonstrate that nuclear CD38 (nCD38) controls glucagon-induced gluconeogenesis in primary hepatocytes and liver in a manner distinct from CD38 occurring in the cytoplasm and lysosomal compartments. We found that the localization of CD38 in the nucleus is required for glucose production by glucagon and that nCD38 activation requires NAD+ supplied by PKCδ-phosphorylated connexin 43. In fasting and diabetes, nCD38 promotes sustained Ca2+ signals via transient receptor potential melastatin 2 (TRPM2) activation by ADP-ribose, which enhances the transcription of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase 1. These findings shed light on the role of nCD38 in glucagon-induced gluconeogenesis and provide insight into nuclear Ca2+ signals that mediate the transcription of key genes in gluconeogenesis under physiological conditions.
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spelling doaj.art-b2d86bd2e6ed4d5f82c454d911976f002023-08-06T11:08:03ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132023-07-015571492150510.1038/s12276-023-01034-9CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetesSo-Young Rah0Yeonsoo Joe1Jeongmin Park2Stefan W. Ryter3Chansu Park4Hun Taeg Chung5Uh-Hyun Kim6Department of Biochemistry and National Creative Research Laboratory for Ca2+ Signaling Network, Jeonbuk National University, Medical School, Keum-am dongSchool of Biological Sciences, University of UlsanSchool of Biological Sciences, University of UlsanProterris IncDepartment of Biochemistry and National Creative Research Laboratory for Ca2+ Signaling Network, Jeonbuk National University, Medical School, Keum-am dongSchool of Biological Sciences, University of UlsanDepartment of Biochemistry and National Creative Research Laboratory for Ca2+ Signaling Network, Jeonbuk National University, Medical School, Keum-am dongAbstract Hepatic glucose production by glucagon is crucial for glucose homeostasis during fasting, yet the underlying mechanisms remain incompletely delineated. Although CD38 has been detected in the nucleus, its function in this compartment is unknown. Here, we demonstrate that nuclear CD38 (nCD38) controls glucagon-induced gluconeogenesis in primary hepatocytes and liver in a manner distinct from CD38 occurring in the cytoplasm and lysosomal compartments. We found that the localization of CD38 in the nucleus is required for glucose production by glucagon and that nCD38 activation requires NAD+ supplied by PKCδ-phosphorylated connexin 43. In fasting and diabetes, nCD38 promotes sustained Ca2+ signals via transient receptor potential melastatin 2 (TRPM2) activation by ADP-ribose, which enhances the transcription of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase 1. These findings shed light on the role of nCD38 in glucagon-induced gluconeogenesis and provide insight into nuclear Ca2+ signals that mediate the transcription of key genes in gluconeogenesis under physiological conditions.https://doi.org/10.1038/s12276-023-01034-9
spellingShingle So-Young Rah
Yeonsoo Joe
Jeongmin Park
Stefan W. Ryter
Chansu Park
Hun Taeg Chung
Uh-Hyun Kim
CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes
Experimental and Molecular Medicine
title CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes
title_full CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes
title_fullStr CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes
title_full_unstemmed CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes
title_short CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes
title_sort cd38 adp ribose trpm2 mediated nuclear ca2 signaling is essential for hepatic gluconeogenesis in fasting and diabetes
url https://doi.org/10.1038/s12276-023-01034-9
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