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- 저자 : Xianlan Wen (검색결과 2 건)
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CREB/CRTC2 controls GLP‐1‐dependent regulation of glucose homeostasis
Lee, Ji‐,Hyun,Wen, Xianlan,Cho, Hana,Koo, Seung‐,Hoi Federation of American Society for Experimental Bi 2018 The FASEB Journal Vol.32 No.3
<P>Glucagon-like peptide 1 (GLP-1) is a major incretin that controls glucose homeostasis. The secretion of mature GLP-1 is regulated via GPCRs, including bile acid receptor G protein-coupled bile acid receptor 1, which uses cAMP signaling to enhance the exocytosis of GLP-1-containing vesicles. However, the role of cAMP-mediated transcription has not been clearly demonstrated to date. In this study, we explored the role of cAMP response element-binding protein/CREB-regulated transcription coactivator 2 (CREB/CRTC2)-dependent transcription on GLP-1 secretion in the L cells. We found that the reduced CREB/CRTC2 activity impaired the cAMP-dependent increase in GLP-1 secretion, whereas expression of constitutively active CRTC2 increased GLP-1 exocytosis from the L cells. Close investigation revealed that expression of not only proglucagon but also PC1/3, an endopeptidase for GLP-1 maturation, is transcriptionally regulated by CREB/CRTC2. Furthermore, expression of peroxisome proliferator-activating receptor coactivator 1 a is also reduced upon depletion of CRTC2, leading to the decreased expression of oxidative phosphorylation (OxPhos) genes, reduced ATP levels, and calcium concentrations in the L cells. Finally, we observed that intestine-specific CRTC2 knockout mice displayed reduced GLP-1 expression, leading to the lower plasma GLP-1 levels, impaired glucose tolerance, and decreased insulin-containing beta cells in pancreatic islets. Our data show that the CREB/CRTC2-dependent transcriptional pathway is critical for regulating glucose homeostasis by controlling production of GLP-1 from the L cells at the level of transcription, maturation, and exocytosis.</P>
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Seul-Yi Lee,Tuan Anh Vuong,Xianlan Wen,Hyeon-Ju Jeong,Hyun-Kyung So,Ilmin Kwon,Jong-Sun Kang,Hana Cho 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-
The sodium leak channel NALCN is a key player in establishing the resting membrane potential (RMP) in neurons andtransduces changes in extracellular Ca2+ concentration ([Ca2+]e) into increased neuronal excitability as thedownstream effector of calcium-sensing receptor (CaSR). Gain-of-function mutations in the human NALCN gene causeencephalopathy and severe intellectual disability. Thus, understanding the regulatory mechanisms of NALCN isimportant for both basic and translational research. This study reveals a novel mechanism for NALCN regulation byarginine methylation. Hippocampal dentate granule cells in protein arginine methyltransferase 7 (PRMT7)-deficientmice display a depolarization of the RMP, decreased threshold currents, and increased excitability compared to wildtypeneurons. Electrophysiological studies combined with molecular analysis indicate that enhanced NALCN activitiescontribute to hyperexcitability in PRMT7−/− neurons. PRMT7 depletion in HEK293T cells increases NALCN activity byshifting the dose-response curve of NALCN inhibition by [Ca2+]e without affecting NALCN protein levels. In vitromethylation studies show that PRMT7 methylates a highly conserved Arg1653 of the NALCN gene located in thecarboxy-terminal region that is implicated in CaSR-mediated regulation. A kinase-specific phosphorylation siteprediction program shows that the adjacent Ser1652 is a potential phosphorylation site. Consistently, our data fromsite-specific mutants and PKC inhibitors suggest that Arg1653 methylation might modulate Ser1652 phosphorylationmediated by CaSR/PKC-delta, leading to [Ca2+]e-mediated NALCN suppression. Collectively, these data suggest thatPRMT7 deficiency decreases NALCN methylation at Arg1653, which, in turn, decreases CaSR/PKC-mediated Ser1652phosphorylation, lifting NALCN inhibition, thereby enhancing neuronal excitability. Thus, PRMT7-mediated NALCNinhibition provides a potential target for the development of therapeutic tools for neurological diseases.
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