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Independent Effects of γ-Aminobutyric Acid Transaminase (GABAT) on Metabolic and Sleep Homeostasis.
Maguire, Sarah E; Rhoades, Seth; Chen, Wen-Feng; Sengupta, Arjun; Yue, Zhifeng; Lim, Jason C; Mitchell, Claire H; Weljie, Aalim M; Sehgal, Amita.
Afiliación
  • Maguire SE; From the Departments of Neuroscience and.
  • Rhoades S; the Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-5158.
  • Chen WF; the Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, and.
  • Sengupta A; the Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-5158.
  • Yue Z; the Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, and.
  • Lim JC; Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
  • Mitchell CH; Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Physiology, Perelman School of Medicine, and.
  • Weljie AM; the Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-5158.
  • Sehgal A; From the Departments of Neuroscience and the Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, and the Department of Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6064 amita@mail.med.upenn.edu.
J Biol Chem ; 290(33): 20407-16, 2015 Aug 14.
Article en En | MEDLINE | ID: mdl-26124278
ABSTRACT
Breakdown of the major sleep-promoting neurotransmitter, γ-aminobutyric acid (GABA), in the GABA shunt generates catabolites that may enter the tricarboxylic acid cycle, but it is unknown whether catabolic by-products of the GABA shunt actually support metabolic homeostasis. In Drosophila, the loss of the specific enzyme that degrades GABA, GABA transaminase (GABAT), increases sleep, and we show here that it also affects metabolism such that flies lacking GABAT fail to survive on carbohydrate media. Expression of GABAT in neurons or glia rescues this phenotype, indicating a general metabolic function for this enzyme in the brain. As GABA degradation produces two catabolic products, glutamate and succinic semialdehyde, we sought to determine which was responsible for the metabolic phenotype. Through genetic and pharmacological experiments, we determined that glutamate, rather than succinic semialdehyde, accounts for the metabolic phenotype of gabat mutants. This is supported by biochemical measurements of catabolites in wild-type and mutant animals. Using in vitro labeling assays, we found that inhibition of GABAT affects energetic pathways. Interestingly, we also observed that gaba mutants display a general disruption in bioenergetics as measured by altered levels of tricarboxylic acid cycle intermediates, NAD(+)/NADH, and ATP levels. Finally, we report that the effects of GABAT on sleep do not depend upon glutamate, indicating that GABAT regulates metabolic and sleep homeostasis through independent mechanisms. These data indicate a role of the GABA shunt in the development of metabolic risk and suggest that neurological disorders caused by altered glutamate or GABA may be associated with metabolic disruption.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sueño / Metabolismo Energético / 4-Aminobutirato Transaminasa / Homeostasis Límite: Animals Idioma: En Año: 2015 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sueño / Metabolismo Energético / 4-Aminobutirato Transaminasa / Homeostasis Límite: Animals Idioma: En Año: 2015 Tipo del documento: Article