Trends in Neurosciences
ReviewCytosolic phospholipase A2 and the distinct transcriptional programs of astrocytoma cells
Section snippets
Phospholipases A2 and the biosynthesis of lipid mediators
Bioactive lipids are important molecules for cell signaling. They include products of the oxidative metabolism of AA, phospholipids in the form of platelet-activating factor, and lysophospholipids in the form of lysophosphatidic acid (LPA). These compounds are biosynthesized through stimulus-coupled liberation of their precursors and subsequent enzymatic conversions. Phospholipase-A2-catalyzed reactions are involved in these metabolic routes, but there are few studies that address the role of
Cytosolic PLA2 is present in astrocytes and has a role in brain pathophysiology
In the human brain, cPLA2 is restricted to the astrocytes of the gray matter20 and, in the murine brain, is confined to astrocytes at the pial surface, which suggests that the involvement of this enzyme in the support of neurotransmission might be provided through its activity in glial cells21. The generation of AA by cPLA2 in astrocytes stimulated by neurotransmitters could therefore be of functional importance for the generation of diffusible messengers that can reach presynaptic terminals,
Muscarinic ACh receptors and AA
Release of AA in response to ACh-receptor agonists has been reported in astrocytoma cells that possess M3 ACh receptors26, and in cells transfected with cDNAs that code for human M1, M3 and M5 ACh receptors1. Although the responses to agonists that engage G-protein-coupled receptors (GPCR) show some overlap, there are several distinct responses for each agonist. Unlike carbachol, both thrombin and lysophosphatidic acid induce cell proliferation. This might be explained by the efficient coupling
Thrombin activates cPLA2
Thrombin is a serine protease that acts in an autocrine or paracrine manner in the nervous system, and is co-localized with its cognate receptors. It induces neurite retraction in neurons, and reversal of stellation, enhancement of the secretion of NGF and mitosis in astrocytes58. Astrocytes in culture are very sensitive to thrombin through activation of the protease-activated receptor (PAR1), and thus show proliferation and morphological changes that are comparable with astrogliosis.
Crosstalk between different isoforms of PLA2
Type IIA PLA2 (sPLA2) is widely distributed in human tissues and its levels are increased by pro-inflammatory stimuli such as bacterial endotoxins and cytokines. Studies in neural cells have shown an interplay between neurotransmitter-activated cPLA2 and sPLA2. Thus, sPLA2 elicits both toxicity and AA release in neural cells, an effect that is synergistic with that of glutamate, and suggests that glutamate-mediated neurotransmission might involve the co-release of glutamate and sPLA2 (Ref. 65).
TNFα directs AA towards prostanoid production
Tumor necrosis factor α (TNFα) elicits responses via two receptors of 55 kDa (TNFR1) and 75 kDa (TNFR2). Sequence homologies in the extracellular region of TNFR1 have related this receptor to the low-affinity receptor for NGF, thus indicating that some of the signaling events related to TNFR1 are also relevant to other factors that act on neural cells. Deletion analysis in the C-terminal intracellular region of the TNFR1 has revealed the existence of a so-called ‘death domain’, which is
Concluding remarks
Astrocytoma cells possess a variety of functional receptors that convey signals to both the cytoplasm and the nucleus. The MAP-kinase cascade is a pathway where regulatory inputs associated to membrane receptors converge. Among the cytosolic proteins that contain the consensus sequence for phosphorylation by MAP kinases, cPLA2 has a central role as it is involved in the release of AA produced by hormones, neurotransmitters and growth factors. Experiments with different agonists and selective
Acknowledgements
The authors thank Tomas Mustelin for his critical reading of the manuscript. Marita Hernández is the recipient of a grant from CSIC-Glaxo. The authors' research is supported by Plan Nacional de Salud y Farmacia (Grant SAF98/0176), Comisión Interministerial de Ciencia y Tecnologı́a and European Commission (Grant 1FD97-0590).
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