Abstract
Astrocytes are increasingly perceived as active partners in physiological brain function and behaviour. The structural correlations of the glia–synaptic interaction are the peripheral astrocyte processes (PAPs), where ezrin and radixin, the two astrocytic members of the ezrin-radixin-moesin (ERM) family of proteins are preferentially localised. While the molecular mechanisms of ERM (in)activation appear universal, at least in mammalian cells, and have been studied in great detail, the actual ezrin and radixin kinases, phosphatases and binding partners appear cell type specific and may be multiplexed within a cell. In astrocytes, ezrin is involved in process motility, which can be stimulated by the neurotransmitter glutamate, through activation of the glial metabotropic glutamate receptors (mGluRs) 3 or 5. However, it has remained open how this mGluR stimulus is transduced to ezrin activation. Knowing upstream signals of ezrin activation, ezrin kinase(s), and membrane-bound binding partners of ezrin in astrocytes might open new approaches to the glial role in brain function. Ezrin has also been implicated in invasive behaviour of astrocytomas, and glial activation. Here, we review data pertaining to potential molecular interaction partners of ezrin in astrocytes, with a focus on PKC and GRK2, and in gliomas and other diseases, to stimulate further research on their potential roles in glia-synaptic physiology and pathology.
Highlights
Astrocytes are a major cell population present throughout all regions in the CNS
The direct mGluR3 or 5 dependent ezrin phosphorylation has not been tested [22], this indicates that ezrin phosphorylation may be mediated by mGluR3 or 5 stimulation. This is supported in astrocytes by the induction of ezrin phosphorylation by the G protein-coupled receptor (GPCR) kinase (GRK) GRK2, which is coupled to mGluR5 [41], but again a direct link between mGluR5 stimulation and ezrin phosphorylation has not been demonstrated [41]
Ezrin is involved in the regulation of glial glutamate uptake though not yet fully understood participation in a protein complex comprising GLAST, NHERF1, and glial fibrillary acidic protein (GFAP)
Summary
Astrocytes are a major cell population present throughout all regions in the CNS. Over the past twenty-five years, the understanding of the astrocyte has shifted from a passive cell type supplying structural and metabolic support to neurons, such as ion homeostasis, neurotransmitter clearance, and energy supply, to an active player in cell-to-cell communication. The structural correlation of the glia–synaptic interaction are the peripheral astrocyte processes (PAPs [6]) These processes extend from the glial main processes, which contain glial fibrillary acidic protein (GFAP) positive glial filaments, and can be very small, down to the dimensions of pure membrane appositions (50–100 nm). Membrane-bound proteins important in cell-to-cell, often glia-neuronal interactions are preferentially localised if not restricted to the PAPs (for example CD44, see below). Based on these structural and biochemical properties the PAP can be regarded as a cellular compartment [6,10]. As an important property of this astrocyte compartment, we have shown that it is selectively visualised by ezrin or radixin, two members of the ezrin radixin, moesin (ERM) family of proteins [13]
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