![]() ![]() GABA BRs are obligate heterodimers composed of GABA B1 and GABA B2 subunits (Evenseth et al., 2020). Unlike GABA ARs, GABA BRs, belonging to class C of G-protein coupled receptors (GPCRs), mediate slow and prolonged inhibitory signaling in the brain via the activation of Gi/o type G-proteins, thus lead to inhibition of adenylyl cyclase (AC Munk et al., 2016). The Cl −-mediated depolarization results in an influx of Ca 2+ from the extracellular space through L- and T-type voltage-gated calcium channels (VGCC Young et al., 2010). Extracellular GABA can activate astroglial GABA ARs to open Cl − channels in astrocytes in primary cell culture and rodent hippocampal slices (Kettenmann et al., 1987 MacVicar et al., 1989). A recent study on human brains reported expressions of genes encoding α 2, β 1, and γ 1 subunits in astrocytes, indicating the existence of functional astroglial α2β1γ1 receptors in humans (Sequeira et al., 2019). The mRNAs of many GABA ARs subunits including α 1–5, β 1–3, γ 1–3, and δ have been detected in cultured primary astrocytes isolated from rodent cerebella (Bovolin et al., 1992 Zheng et al., 1993). Although the exact types of astroglial GABA ARs in the brain have not been clearly distinguished, functional GABA ARs have been found on astrocytes (Fraser et al., 1995). The structure diversity confers GABA ARs with distinct topology, channel kinetics, affinity for GABA, rate of desensitization, and ability for transient chemical modification such as phosphorylation (Mohler, 2006). Indeed, about 20 widely occurring native GABA ARs have been identified, with the major combinations being α 1β 2/3γ 2, α 2β 3γ 2, α 3β 3γ 2 (Barnard et al., 1998 Mohler, 2006). The GABA AR family comprises 19 discovered subunits: α 1–6, β 1–3, γ 1–3, ρ 1–3, δ, ε, π, and θ, and the subunit combinations lead to a great diversity of GABA ARs (Olsen and Sieghart, 2008, 2009 Sequeira et al., 2019). Each subunit has a large extracellular N-terminal domain, three membrane spanning domains (M1-3), an intracellular loop of variable length, and a fourth membrane spanning domain (M4) with extracellular C-terminal end. ![]() ![]() The GABA ARs consist of five protein subunits arranged around a central pore that constitutes the ion channel. Astrocytes express both GABA ARs and GABA BRs in the soma, the synapse-surrounding processes, and the brain vessel-contacting endfeet (Nilsson et al., 1993 Charles et al., 2003 Meier et al., 2008). Astrocytes are also with GABA uptake capacity which requires at least two sodium ions per transportable GABA molecule ( Figure 1 Larsson et al., 1980). GABA is the main inhibitory transmitter in adults, which binds to GABA receptors (ionotropic GABA A receptors, GABA ARs and metabotropic GABA B receptors, GABA BRs) on neurons and inhibits neuronal activities via reducing exocytosis, hyperpolarizing membranes, and shunting depolarization. Astrocytes also contain a considerable amount of GABA that can be released to modulate the activities of GABA receptors-expressing cells, indicating a GABAergic role of astrocytes (Le Meur et al., 2012 Yoon et al., 2012).Īstrocytes Internalize GABA via GABA Receptors and Transporters Astrocytes express GABA receptors to interact with an extracellular GABA, suggesting astrocytes as GABAceptive cells (Le Meur et al., 2012 Yoon et al., 2012). In the recent decade, gamma-aminobutyric acid (GABA) has emerged as a novel gliotransmitter (Yoon and Lee, 2014). More importantly, astrocytes directly regulate synaptic plasticity and synaptic transmission by releasing gliotransmitters such as glutamate, adenosine triphosphate (ATP), taurine, glycine, and D-serine (Barakat and Bordey, 2002 Hussy, 2002 Henneberger et al., 2010 Bernardinelli et al., 2014 Mederos and Perea, 2019). Astrocytes induce synaptic formation, regulate the release and uptake of synaptic neurotransmitters, and maintain synaptic cleft transmitter homeostasis (Allen, 2014). They form complex connections with neurons, blood vessels, and other glial cells, and play an important role in preserving normal brain functions via providing energy and nutritional support for neurons, maintaining metabolic homeostasis of the CNS, and regulating cerebral blood flow (Anderson and Nedergaard, 2003 Bélanger et al., 2011 Scheiber and Dringen, 2013).Ī single astrocyte can touch more than 100,000 synapses in the mouse cortex via a tripartite synapse, a structure that the astrocyte associates with the pre- and post-synapse areas of neurons (Bushong et al., 2002). Astrocytes, the most abundant glial cells in the central nervous system (CNS), account for about 20% of the glial cells in the neocortex of the human brain (Pelvig et al., 2008). ![]()
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