The unique mechanism of EAAT anion channel gating

The unique mechanism of EAAT anion channel gating results in neuronal or glial anion conductances that follow changes in substrate concentrations and thus allow feedback control of glutamate release (Wersinger et al., 2006) or modification of GABAergic postsynaptic currents by glutamatergic signals (Winter et al., 2012). Moreover, it explains why isoform-specific variations in glutamate transport by EAATs result in the formation of anion channels that preferentially open or close within their physiological voltage range (Schneider et al., 2014). Recently, gain-of-function mutations in genes encoding EAAT anion channels have been linked to pathological neuronal excitability and cell-volume regulation (Winter et al., 2012). EAAT anion channel activity is also enhanced under conditions of increased synaptic glutamate concentration and may thus contribute to the clinical symptoms associated with Okadaic acid ischemia or certain neurodegenerative diseases. The structural and mechanistic data presented here might help in the design of EAAT anion channel modulators and thus open therapeutic avenues to correct the cellular defects linked to these pathological conditions.
Experimental Procedures
Author Contributions
Acknowledgments
Introduction Astrocytes are a heterogeneous class of neuroectodermally derived glial cells that arise from the neural crest and are present in the central nervous systems of all vertebrates. Whilst the term “astrocyte” is only applicable to vertebrates, homologous cells termed “gliocytes” or perineuronal glia are evident in all invertebrates that have a nervous system, including groups such as jellyfish that possess only a simple nerve net. The debate as to what constitutes an astrocyte is ongoing; thus, the ependymoglia (glia-like cells that contact the ventricles) often exhibit some astrocyte-like features (Kettenmann and Ransom, 1995) but are not routinely thought of as astrocytes. Conversely the convergence of anatomical phenotype between radial glia (such as the Bergmann glial cells of the cerebellum) and the elongated radially oriented astrocytes present in areas such as the supraoptic nucleus (Bonfanti and Poulain, 1993) and their capacity to differentiate into astrocytes, have contributed to suggestions that radial glia be classified more broadly as astrocytes (Kimelberg, 2010). It is probable that future classifications of astrocytes will recognise many cells with a continuum of functions, phenotypes and cellular origins under the broad descriptor “astrocyte” rather than placing an emphasis on a few discreet categories. Within currently accepted constraints there are multiple ways to classify astrocytes, based upon (but not limited to) features such as (i) lineage and antigenic phenotype, (ii) anatomical classifications such as the neuronal compartments that the astrocytes physically or biochemically support (such as axons or synapses, etc.) and (iii) expression of proteins such as glutamate transporters and receptors that allow specific astrocytes to respond to, and influence their environment. An extensive discourse is outside the limits of this review, but as a generalisation most astrocytes can be assigned into two categories: (i) fibrous astrocytes which are abundant in white matter tracts, contain many intermediate filaments (visible at the electron microscope level) and are usually strongly immunoreactive for the intermediate filament protein glial fibrillary acidic protein (GFAP) (Pekny and Pekna, 2004). Protoplasmic astrocytes are typically present in grey matter and peripheral regions of white matter tracts; the name for these cells stems from the now outdated use of the word “protoplasm” to describe a poorly stained cytoplasm of cells. This includes the cytoplasm of astrocytes that lack a significant content of GFAP fibrils, (Fig. 1) unless they are stimulated. The presence of intermediate filament proteins in a cell and their assembly into filaments will obviously have structural and possibly biochemical implications for the cell. Whilst there is abundant evidence for enhanced expression of GFAP in response to a wide variety of insults, the functional roles played by GFAP are unclear. GFAP knockout mice do appear to exhibit increased sensitivity to insults and this appears to reconcile with the idea that GFAP serves as an anchor for the glial glutamate transporter GLAST (which may be important in minimising excitotoxicity in the brain). Disruption of this GFAP–GLAST interaction leads to deficits in glutamate homeostasis (Sullivan et al., 2007).