CD38-mediated Ca2+ signaling contributes to glucagon-induced hepatic gluconeogenesis

So-Young Rah,Uh-Hyun Kim

doi:10.1038/srep10741

Abstract

CD38 is a multifunctional enzyme for the synthesis of Ca2+ second messengers. Glucagon promotes hepatic glucose production through Ca2+ 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 Ca2+ increases via CD38 in hepatocytes. 8-Br-cADPR, an antagonistic cADPR analog, completely blocked glucagon-induced Ca2+ increases and phosphorylation of cAMP response element-binding protein (CREB). Moreover, glucagon-induced sustained Ca2+ 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 Ca2+ 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.

Highlights

In this study, we investigated whether CD38 is activated to produce a Ca2+ second messenger in the glucagon signaling of hepatocytes
In response to glucagon treatment, cyclic ADP-ribose (cADPR) levels were increased in HCs from wild type (WT) mice, while cADPR was not produced in HCs from CD38−/− mice (Fig. 1c)
Our data demonstrate for the first time that cADPR-mediated Ca2+ signals, via the activation of CD38, regulates hepatic gluconeogenic gene expression and hepatic glucose productions (HGP)

Summary

Introduction

We investigated whether CD38 is activated to produce a Ca2+ second messenger in the glucagon signaling of hepatocytes. Our data show that CD38 plays a critical role in glucagon-induced glucose production by producing cADPR in hepatocytes. We addressed the question of whether cADPR-mediated Ca2+ increase induces glucose production by measuring glucose levels in HCs from WT and CD38−/− mice.

Results

Conclusion