Abstract
Lysophosphatidic acid (LPA) is an extracellular lipid mediator that regulates nervous system development and functions acting through G protein-coupled receptors (GPCRs). Here we explore the crosstalk between LPA1 receptor and glutamatergic transmission by examining expression of glutaminase (GA) isoforms in different brain areas isolated from wild-type (WT) and KOLPA1 mice. Silencing of LPA1 receptor induced a severe down-regulation of Gls-encoded long glutaminase protein variant (KGA) (glutaminase gene encoding the kidney-type isoforms, GLS) protein expression in several brain regions, particularly in brain cortex and hippocampus. Immunohistochemical assessment of protein levels for the second type of glutaminase (GA) isoform, glutaminase gene encoding the liver-type isoforms (GLS2), did not detect substantial differences with regard to WT animals. The regional mRNA levels of GLS were determined by real time RT-PCR and did not show significant variations, except for prefrontal and motor cortex values which clearly diminished in KO mice. Total GA activity was also significantly reduced in prefrontal and motor cortex, but remained essentially unchanged in the hippocampus and rest of brain regions examined, suggesting activation of genetic compensatory mechanisms and/or post-translational modifications to compensate for KGA protein deficit. Remarkably, Golgi staining of hippocampal regions showed an altered morphology of glutamatergic pyramidal cells dendritic spines towards a less mature filopodia-like phenotype, as compared with WT littermates. This structural change correlated with a strong decrease of active matrix-metalloproteinase (MMP) 9 in cerebral cortex and hippocampus of KOLPA1 mice. Taken together, these results demonstrate that LPA signaling through LPA1 influence expression of the main isoenzyme of glutamate biosynthesis with strong repercussions on dendritic spines maturation, which may partially explain the cognitive and learning defects previously reported for this colony of KOLPA1 mice.
Highlights
Lysophosphatidic acid (LPA; 1 or 2-acyl-sn-glycero-3phosphate) is a naturally occurring lysophospholipid derived from cell membranes that belongs to the growing list of bioactive lipids
Four different GA isoenzymes are expressed in mammalian brain (Márquez et al, 2016): Gls-encoded long glutaminase protein variant (KGA) and glutaminase gene encoding the kidney-type isoforms (Gls)-encoded short glutaminase protein variant (GAC) proteins are encoded by the Gls gene (GLS isoforms), whilst glutaminase gene encoding the liver-type isoforms (Gls2)-encoded long glutaminase protein variant (GAB) and Gls2-encoded short glutaminase protein variant (LGA) arise from the Gls2 gene (GLS2 isoforms; Aledo et al, 2000; Matés et al, 2013)
The influence of silencing LPA1 receptor on brain GA protein expression was assessed by immunohistochemistry of the KGA and GLS2 (GAB/LGA) isoforms
Summary
Lysophosphatidic acid (LPA; 1 or 2-acyl-sn-glycero-3phosphate) is a naturally occurring lysophospholipid derived from cell membranes that belongs to the growing list of bioactive lipids. It may act as an intercellular signaling molecule after recognition by G protein-coupled receptor(s) (GPCRs). LPA is enriched in brain tissue, produced by platelets and cells from the nervous system and is found in serum (Choi and Chun, 2013; Yung et al, 2015). Multiple cellular responses have been reported for this bioactive natural lipid in the central nervous system (CNS) as well as in neural cell lines. LPA-primed astrocytes promote neuronal differentiation of cerebral cortical progenitors and developing cortical neurons, which showed increases in arborization and neurite outgrowth (Spohr et al, 2008, 2011)
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