Independent Effects of γ-Aminobutyric Acid Transaminase (GABAT) on Metabolic and Sleep Homeostasis.

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.

• Authors: Sarah E Maguire, Seth Rhoades, Wen-Feng Chen, Arjun Sengupta, Zhifeng Yue, Jason C Lim, Claire H Mitchell, Aalim M Weljie, Amita Sehgal
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 33 Pg. 20407-16 (Aug 14 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26124278 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Ketoglutaric Acids
• Glutamic Acid
• 4-Aminobutyrate Transaminase

Topics

• 4-Aminobutyrate Transaminase (genetics, metabolism)
• Animals
• Brain (enzymology, metabolism, physiology)
• Drosophila melanogaster
• Energy Metabolism
• Glutamic Acid (metabolism)
• Homeostasis
• Ketoglutaric Acids (metabolism)
• Mutation
• Oxidative Stress
• Sleep