Brain glutaminases

Abstract

Glutaminase is considered as the main glutamate producer enzyme in brain. Consequently, the enzyme is essential for both glutamatergic and gabaergic transmissions. Glutaminederived glutamate and ammonia, the products of glutaminase reaction, fulfill crucial roles in energy metabolism and in the biosynthesis of basic metabolites, such as GABA, proteins and glutathione. However, glutamate and ammonia are also hazardous compounds and danger lurks in their generation beyond normal physiological thresholds; hence, glutaminase activity must be carefully regulated in the mammalian brain. The differential distribution and regulation of glutaminase are key factors to modulate the metabolism of glutamate and glutamine in brain. The discovery of novel isoenzymes, protein interacting partners and subcellular localizations indicate new functions for brain glutaminase. In this short review, we summarize recent findings that point consistently towards glutaminase as a multifaceted protein able to perform different tasks. Finally, we will highlight the involvement of glutaminase in pathological states and its consideration as a potential therapeutic target.

Expression of Gls and Gls2 glutaminase isoforms in astrocytes

“…Finally, we addressed the identification and quantitation of GA transcripts expressed by rat astrocytes. A real‐time RT‐PCR (qRT‐PCR) method was devised targeting the four GA isoforms so far reported to be expressed in mammalian tissues (Márquez et al, ; Martín‐Rufián et al, ). Total RNA was extracted from astrocytes isolated from rat cerebellum, a region where we found a significant population of cells positive for GA activity staining.…”

“…This fact easily illustrates how astrocytes can modulate expression of GA isoforms, depending on the environmental conditions to which are they exposed, to maintain their energy and metabolic homeostasis. Mammalian KGA and GAB proteins possess different kinetic and regulatory properties; therefore, they reach full catalytic activity at different cellular concentrations of Gln, Glu, and Pi (Márquez et al, ). In this work, we have shown functional GA activity in the cytoplasm of discrete populations of hippocampal and cerebellar astrocytes, which can be ascribed to mitochondrial GA.…”

Mammalian Glutaminase Gls2 Gene Encodes Two Functional Alternative Transcripts by a Surrogate Promoter Usage Mechanism

“…The same authors reported that about 52% of the total human genes were subject to regulation by putative alternative promoters, and genes encoding signal-transduction related proteins were more likely to display alternative promoters. It is tempting to speculate that GLS2 transcripts may have this kind of regulatory mechanism in brain because the function of GAB and LGA transcripts might be associated to signaling or regulatory functions, besides their role as glutamate-producer enzymes [28], [43].…”

Glutaminases in brain: Multiple isoforms for many purposes

“…Doublelabeling revealed that GIP and GLS2 colocalized in astrocytes cell bodies and processes, including their perivascular end feet (Olalla et al, 2008). Considering the key role of astrocytes in cerebrovascular regulation (Iadecola and Nedergaard, 2007;Koehler et al, 2006), the GIP-GLS2 interaction might be implicated in this regulation throughout the synthesis of Glu, a vasoactive compound (Márquez et al, 2010).…”