title: CD38-mediated Ca(2+) signaling contributes to glucagon-induced hepatic gluconeogenesis.
abstract: CD38 is a multifunctional enzyme for the synthesis of Ca(2+) second messengers. Glucagon promotes hepatic glucose production through Ca(2+) signaling in the fasting condition. In this study, we investigated the role of CD38 in the glucagon signaling of hepatocytes. Here, we show that glucagon induces cyclic ADP-ribose (cADPR) production and sustained Ca(2+) increases via CD38 in hepatocytes. 8-Br-cADPR, an antagonistic cADPR analog, completely blocked glucagon-induced Ca(2+) increases and phosphorylation of cAMP response element-binding protein (CREB). Moreover, glucagon-induced sustained Ca(2+) signals and translocation of CREB-regulated transcription coactivator 2 to the nucleus were absent and glucagon-induced glucose production and expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (Pck1) are remarkably reduced in hepatocytes from CD38(-/-) mice. Furthermore, in the fasting condition, CD38(-/-) mice have decreased blood glucose and hepatic expression of G6Pase and Pck1 compared to wild type mice. Our data suggest that CD38/cADPR-mediated Ca(2+) signals play a key role in glucagon-induced gluconeogenesis in hepatocytes, and that the signal pathway has significant clinical implications in metabolic diseases, including type 2 diabetes.
authors.affiliation: Department of Biochemistry and National Creative Research Laboratory for Ca2+ signaling Network.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Rah
authors.affiliation: 1] Department of Biochemistry and National Creative Research Laboratory for Ca2+ signaling Network [2] The Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, 561-182.
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose; D020013:Calcium Signaling / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000378:metabolism* / Q000494:pharmacology; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000096:biosynthesis; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D036563:Cyclic ADP-Ribose; D005934:Glucagon; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D005952:Glucose-6-Phosphatase; D051997:ADP-ribosyl Cyclase 1; D005947:Glucose