4.7 Article

Impact of Inhibition of Glutamine and Alanine Transport on Cerebellar Glial and Neuronal Metabolism

Journal

BIOMOLECULES
Volume 12, Issue 9, Pages -

Publisher

MDPI
DOI: 10.3390/biom12091189

Keywords

glutamine; alanine; amino acid transporters

Funding

  1. Australian Research Council [DP180101702]

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This study examined the cycling of glutamine and alanine in the cerebellum by inhibiting amino acid transporters. The results indicate that the cerebellum has tightly coupled cells and that glutamate/glutamine, as well as alanine cycling, play a major role in this part of the brain.
5The cerebellum, or little brain, is often overlooked in studies of brain metabolism in favour of the cortex. Despite this, anomalies in cerebellar amino acid homeostasis in a range of disorders have been reported. Amino acid homeostasis is central to metabolism, providing recycling of carbon backbones and ammonia between cell types. Here, we examined the role of cerebellar amino acid transporters in the cycling of glutamine and alanine in guinea pig cerebellar slices by inhibiting amino acid transporters and examining the resultant metabolism of [1-C-1(3)]D-glucose and [1,2-C-1(3)]acetate by NMR spectroscopy and LCMS. While the lack of specific inhibitors of each transporter makes interpretation difficult, by viewing results from experiments with multiple inhibitors we can draw inferences about the major cell types and transporters involved. In cerebellum, glutamine and alanine transfer is dominated by system A, blockade of which has maximum effect on metabolism, with contributions from System N. Inhibition of neural system A isoform SNAT1 by MeAIB resulted in greatly decreased metabolite pools and reduced net fluxes but showed little effect on fluxes from [1,2-C-13]acetate unlike inhibition of SNAT3 and other glutamine transporters by histidine where net fluxes from [1,2-C-1(3)]acetate are reduced by similar to 50%. We interpret the data as further evidence of not one but several glutamate/glutamine exchange pools. The impact of amino acid transport inhibition demonstrates that the cerebellum has tightly coupled cells and that glutamate/glutamine, as well as alanine cycling, play a major role in that part of the brain.

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