---
OA_place: publisher
OA_type: hybrid
PlanS_conform: '1'
_id: '21860'
abstract:
- lang: eng
text: Glutamate excitotoxicity is a cell death mechanism triggered by accumulation
of glutamate in the extracellular space. The α-ketoglutarate dehydrogenase complex
(αKGDHC), an enzyme of the tricarboxylic acid cycle, represents a branching point
controlling glutamate formation and its consumption as a fuel. Hence, modulation
of the activity of αKGDHC might alter the amount of glutamate available for excitotoxic
effects. To address this hypothesis, hippocampal neurons in primary co-culture
with glial cells were exposed to zero-Mg2 buffer to elicit excitotoxicity through
N-methyl-D-aspartic acid (NMDA) receptor disinhibition. Pretreatment of the cultures
with succinyl phosphonate, to inhibit αKGDHC, enhanced excitotoxity, whereas promotion
of αKGDHC activity by pretreatment with thiamine caused an opposite action. Moreover,
NMDA receptor currents – but not those mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptors – were potentiated in neurons with impaired αKGDHC activity
and diminished in neurons with boosted αKGDHC activity. The sensitization of NMDA
receptors involved mGluR1 activation and was accompanied by enhanced neuronal
discharge activity, elevated basal cytosolic Ca2+ levels, and augmented Ca2+ responses
evoked by glutamate application. These results suggest that mGluR1-mediated potentiation
of NMDA receptors contributes to a mechanism by which inhibition of αKGDHC might
exacerbate glutamate excitotoxicity.
acknowledgement: The technical assistance by Tanja Wagner and Elena Lilliu is gratefully
acknowledged. This research was funded in whole or in part by the Austrian Science
Fund (FWF) (P36145 to H.K., PAT8605623 to M.H. and P33799 to A.V.K.]. Open Access
funding provided by Medical University of Vienna and the Austrian Science Fund (FWF).
Deposited in PMC for immediate release.
article_number: jcs264420
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Vanessa
full_name: Goeschl, Vanessa
last_name: Goeschl
- first_name: Matej
full_name: Hotka, Matej
last_name: Hotka
- first_name: Bernhard
full_name: Hochreiter, Bernhard
id: e6cab3de-17f6-11ed-9210-c1e42e045e9d
last_name: Hochreiter
- first_name: Karlheinz
full_name: Hilber, Karlheinz
last_name: Hilber
- first_name: Stefan
full_name: Boehm, Stefan
last_name: Boehm
- first_name: Andrey V.
full_name: Kozlov, Andrey V.
last_name: Kozlov
- first_name: Helmut
full_name: Kubista, Helmut
last_name: Kubista
citation:
ama: Goeschl V, Hotka M, Hochreiter B, et al. α-ketoglutarate dehydrogenase complex
activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA
receptors in primary cultures. Journal of Cell Science. 2026;139(8). doi:10.1242/jcs.264420
apa: Goeschl, V., Hotka, M., Hochreiter, B., Hilber, K., Boehm, S., Kozlov, A. V.,
& Kubista, H. (2026). α-ketoglutarate dehydrogenase complex activity modulates
glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary
cultures. Journal of Cell Science. The Company of Biologists. https://doi.org/10.1242/jcs.264420
chicago: Goeschl, Vanessa, Matej Hotka, Bernhard Hochreiter, Karlheinz Hilber, Stefan
Boehm, Andrey V. Kozlov, and Helmut Kubista. “α-Ketoglutarate Dehydrogenase Complex
Activity Modulates Glutamate Excitotoxicity via Metabotropic Regulation of NMDA
Receptors in Primary Cultures.” Journal of Cell Science. The Company of
Biologists, 2026. https://doi.org/10.1242/jcs.264420.
ieee: V. Goeschl et al., “α-ketoglutarate dehydrogenase complex activity
modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors
in primary cultures,” Journal of Cell Science, vol. 139, no. 8. The Company
of Biologists, 2026.
ista: Goeschl V, Hotka M, Hochreiter B, Hilber K, Boehm S, Kozlov AV, Kubista H.
2026. α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity
via metabotropic regulation of NMDA receptors in primary cultures. Journal of
Cell Science. 139(8), jcs264420.
mla: Goeschl, Vanessa, et al. “α-Ketoglutarate Dehydrogenase Complex Activity Modulates
Glutamate Excitotoxicity via Metabotropic Regulation of NMDA Receptors in Primary
Cultures.” Journal of Cell Science, vol. 139, no. 8, jcs264420, The Company
of Biologists, 2026, doi:10.1242/jcs.264420.
short: V. Goeschl, M. Hotka, B. Hochreiter, K. Hilber, S. Boehm, A.V. Kozlov, H.
Kubista, Journal of Cell Science 139 (2026).
date_created: 2026-05-11T10:52:27Z
date_published: 2026-04-27T00:00:00Z
date_updated: 2026-05-12T06:40:18Z
day: '27'
ddc:
- '570'
department:
- _id: Bio
doi: 10.1242/jcs.264420
external_id:
pmid:
- '41834724'
file:
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creator: dernst
date_created: 2026-05-12T06:27:54Z
date_updated: 2026-05-12T06:27:54Z
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intvolume: ' 139'
issue: '8'
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
pmid: 1
publication: Journal of Cell Science
publication_identifier:
eissn:
- 1477-9137
issn:
- 0021-9533
publication_status: published
publisher: The Company of Biologists
quality_controlled: '1'
scopus_import: '1'
status: public
title: α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity
via metabotropic regulation of NMDA receptors in primary cultures
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 139
year: '2026'
...