Chloride Channels in Astrocytes: Structure, Roles in Brain Homeostasis and Implications in Disease

Abstract

Astrocytes are the most abundant cell type in the CNS (central nervous system). They exert multiple functions during development and in the adult CNS that are essential for brain homeostasis. Both cation and anion channel activities have been identified in astrocytes and it is believed that they play key roles in astrocyte function. Whereas the proteins and the physiological roles assigned to cation channels are becoming very clear, the study of astrocytic chloride channels is in its early stages. In recent years, we have moved from the identification of chloride channel activities present in astrocyte primary culture to the identification of the proteins involved in these activities, the determination of their 3D structure and attempts to gain insights about their physiological role. Here, we review the recent findings related to the main chloride channels identified in astrocytes: the voltage-dependent ClC-2, the calcium-activated bestrophin, the volume-activated VRAC (volume-regulated anion channel) and the stress-activated Maxi-Cl−. We discuss key aspects of channel biophysics and structure with a focus on their role in glial physiology and human disease.

Development and validation of a potent and specific inhibitor for the CLC-2 chloride channel

“…Our finding that inhibition of CLC-2 causes a downregulation of network activity is the opposite of expected based on a causal link between CLC-2 loss-offunction and epilepsy; rather, our data implicate CLC-2 as a putative target for anti-epileptics. Despite the unexpected nature of this finding, there are many potential mechanisms that might result in the anti-epileptic effects of CLC-2 inhibition, including intrinsic, e.g., alteration in neuronal excitability 63 , extrinsic (non-neuronal, e.g., astrocytic 68 ), or synaptic 48 , among others. Our discovery of AK-42, a potent and specific CLC-2 inhibitor, will enable future studies to determine the mechanism by which CLC-2 regulates excitability.…”

Reconstituted Mining Effluent Reduces Neuronal Proliferation in the Developing Brain and Slows Growth of Body and Facial Features in Wild-Caught Wood Frog Tadpoles

“…Superficially one may predict that chloride-based mining effluent treatment would have greater effects on brain development than sulfate-based treatment, due to the fact that chloride is a critical ion for normal brain function (Elorza-Vidal, Gaitán-Peñas, & Estévez, 2019). The fact that chloride-based treatment only affected the brain at 14 days and only at the highest concentration demonstrates that the tadpole nervous system is particularly resistant to high levels of chloride exposure.…”

Single-molecule FRET monitors CLC transporter conformation and subunit independence

“…These homologs reside in intracellular membranes, including lysosomes, endosomes, osteoclasts, and synaptic vesicles, where they play critical roles in regulating [Cl -] and [H + ], and where mutations lead to severe pathologies (Poroca et al, 2017;Jentsch and Pusch, 2018;Nicoli et al, 2019;Gianesello et al, 2020). The CLC channel homologs are expressed in the plasma membranes of essentially all cells, carrying out functions ranging from voltage-dependent signaling to epithelial ion transport (Fahlke and Fischer, 2010;Denton et al, 2013;Wang et al, 2017;Fernandes-Rosa et al, 2018;Jentsch and Pusch, 2018;Elorza-Vidal et al, 2019;Stowasser et al, 2019;Altamura et al, 2020).…”