Glucagon-like peptide-1 protects NSC-34 motor neurons against glucosamine through Epac-mediated glucose uptake enhancement

Authors
Jung-Geun LimJang-Jun LeeSung-Hee ParkJae-Hyung ParkSun-Joo KimHo-Chan ChoWon-Ki BaekDae-Kwang KimDae-Kyu Song
Department
Dept. of Physiology (생리학); Dept. of Neurology (신경과학); Dept. of Microbiology (미생물학); Dept. of Medical Genetics (의학유전학); Dept. of Internal Medicine (내과학); Institute for Cancer Research (암연구소)
Issue Date
2010
Citation
Neuroscience Letters, Vol.479(1) : 13-17, 2010
ISSN
0304-3940
Abstract
Bioenergetic deficits are considered a common cause of neurodegenerative diseases. Although creatine supplementation has been shown to be effective in certain neurodegenerative disorders, it is less effective in amyotrophic lateral sclerosis, a disease that primarily affects motor neurons. These neurons are particularly vulnerable to a cellular energy deficit. Using the ATP-depleting drug glucosamine, we evaluated whether the incretin hormone glucagon-like peptide (GLP)-1 protects motor neurons against glucosamine-induced cytotoxicity. Undifferentiated NSC-34 cells were differentiated into glutamate-sensitive motor neurons by a modified serum deprivation technique. Glucosamine inhibited the viability of differentiated NSC-34 cells in a time- and dose-dependent manner. Glucosamine also acutely reduced cellular glucose uptake, glucokinase activity and intracellular ATP levels. As a result, the activity of AMP-activated protein kinase as well as endoplasmic reticulum stress increased. Pretreatment with GLP-1 significantly alleviated glucosamine-mediated neurotoxicity by restoring cellular glucose uptake, glucokinase activity and intracellular ATP levels. The protective effect of GLP-1 was replicated by Exendin-4 but not Exendin-9, and not blocked by inhibitors of phosphoinositide-3 kinase, protein kinase A, cSrc, or epidermal growth factor receptor, but it was blocked by an adenylate cyclase inhibitor. A selective activator for exchange proteins directly activated by cAMP (Epac), but not a selective activator for protein kinase A, mimicked the GLP-1 effect. Therefore GLP-1 may exert its effect mainly through cAMP-dependent, Epac-mediated restoration of glucose uptake that is typically impaired by glucosamine. These findings indicate that GLP-1 could be employed therapeutically to protect motor neurons that are susceptible to bioenergetic deficits. Keywords GLP-1; Motor neuron; Glucosamine; Glucose uptake; Glucokinase; Epac
Keywords
Motor neuronGlucosamineGlucose uptakeGlucokinaseEpacGLP-1
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/33548
Appears in Collections:
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Neurology (신경과학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Microbiology (미생물학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Medical Genetics (의학유전학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
1. Journal Papers (연구논문) > 3. Research Institutues (연구소) > Institute for Cancer Research (암연구소)
Keimyung Author(s)
박재형; 송대규; 임정근; 백원기; 김대광; 조호찬
Full Text
http://lps3.www.sciencedirect.com.proxy.dsmc.or.kr/science/article/pii/S030439401000580X?via%3Dihub
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