Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior
Abstract Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-Glu or l-Gln would impact the γ-aminobutyric acid (GABA) shunt...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-87569-1 |
| _version_ | 1818722846975721472 |
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| author | Adam M. Wawro Chandresh R. Gajera Steven A. Baker Robert K. Leśniak Curt R. Fischer Nay L. Saw Mehrdad Shamloo Thomas J. Montine |
| author_facet | Adam M. Wawro Chandresh R. Gajera Steven A. Baker Robert K. Leśniak Curt R. Fischer Nay L. Saw Mehrdad Shamloo Thomas J. Montine |
| author_sort | Adam M. Wawro |
| collection | DOAJ |
| description | Abstract Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-Glu or l-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous l-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport l-Gln. |
| first_indexed | 2024-12-17T21:01:07Z |
| format | Article |
| id | doaj.art-0b1cf771b7094dddbe45b3302eac42de |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T21:01:07Z |
| publishDate | 2021-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-0b1cf771b7094dddbe45b3302eac42de2022-12-21T21:32:43ZengNature PortfolioScientific Reports2045-23222021-04-0111111310.1038/s41598-021-87569-1Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behaviorAdam M. Wawro0Chandresh R. Gajera1Steven A. Baker2Robert K. Leśniak3Curt R. Fischer4Nay L. Saw5Mehrdad Shamloo6Thomas J. Montine7Department of Pathology, Stanford UniversityDepartment of Pathology, Stanford UniversityDepartment of Pathology, Stanford UniversityChEM-H, Stanford UniversityChEM-H, Stanford UniversityBehavioral and Functional Neuroscience Laboratory, Stanford UniversityBehavioral and Functional Neuroscience Laboratory, Stanford UniversityDepartment of Pathology, Stanford UniversityAbstract Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-Glu or l-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous l-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport l-Gln.https://doi.org/10.1038/s41598-021-87569-1 |
| spellingShingle | Adam M. Wawro Chandresh R. Gajera Steven A. Baker Robert K. Leśniak Curt R. Fischer Nay L. Saw Mehrdad Shamloo Thomas J. Montine Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior Scientific Reports |
| title | Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior |
| title_full | Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior |
| title_fullStr | Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior |
| title_full_unstemmed | Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior |
| title_short | Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior |
| title_sort | enantiomers of 2 methylglutamate and 2 methylglutamine selectively impact mouse brain metabolism and behavior |
| url | https://doi.org/10.1038/s41598-021-87569-1 |
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