Neurochemical Research

, Volume 39, Issue 3, pp 500–515 | Cite as

Heterogeneous Cellular Distribution of Glutamate Dehydrogenase in Brain and in Non-neural Tissues

  • Cleanthe Spanaki
  • Dimitra Kotzamani
  • Zoe Petraki
  • Elias Drakos
  • Andreas Plaitakis


Mammalian glutamate dehydrogenase (GDH) is an evolutionarily conserved enzyme central to the metabolism of glutamate, the main excitatory transmitter in mammalian CNS. Its activity is allosterically regulated and thought to be controlled by the need of the cell for ATP. While in most mammals, GDH is encoded by a single GLUD1 gene that is widely expressed (housekeeping; hGDH1 in the human), humans and other primates have acquired via retroposition a GLUD2 gene encoding an hGDH2 isoenzyme with distinct functional properties and tissue expression profile. Whereas hGDH1 shows high levels of expression in the liver, hGDH2 is expressed in human testis, brain and kidney. Recent studies have provided significant insight into the functional adaptation of hGDH2. This includes resistance to GTP control, enhanced sensitivity to inhibition by estrogens and other endogenous allosteric effectors, and ability to function in a relatively acidic environment. While inhibition of hGDH1 by GTP, derived from Krebs cycle, represents the main mechanism by which the flux of glutamate through this pathway is regulated, dissociation of hGDH2 from GTP control may provide a biological advantage by permitting enzyme function independently of this energy switch. Also, the relatively low optimal pH for hGDH2 is suited for transmitter glutamate metabolism, as glutamate uptake by astrocytes leads to significant mitochondrial acidification. Although mammalian GDH is a housekeeping enzyme, its levels of expression vary markedly among the various tissues and among the different types of cells that constitute the same organ. In this paper, we will review existing evidence on the cellular and subcellular distribution of GDH in neural and non-neural tissues of experimental animals and humans, and consider the implications of these findings in biology of these tissues. Special attention is given to accumulating evidence that glutamate flux through the GDH pathway is linked to cell signaling mechanisms that may be tissue-specific.


Glutamate dehydrogenase hGDH1 hGDH2 Localization Immunohistochemistry Expression profile 



This research has been co-financed by the European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)—Research Funding Program: THALIS –UOA, Title of Grant “Mechanisms of pathogenesis of Parkinson’s disease”, Code 70/3/11679.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Cleanthe Spanaki
    • 1
  • Dimitra Kotzamani
    • 1
  • Zoe Petraki
    • 1
  • Elias Drakos
    • 2
  • Andreas Plaitakis
    • 1
  1. 1.Department of Neurology, Medical SchoolUniversity of CreteHeraklion, CreteGreece
  2. 2.Pathology Department, Medical SchoolUniversity of CreteHeraklion, CreteGreece

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