Abstract
γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the nervous system. It plays a crucial role in many physiological processes. Upon release from the presynaptic element, it is removed from the synaptic cleft by reuptake due to the action of GABA transporters (GATs). GATs belong to a large SLC6 protein family whose characteristic feature is sodium-dependent relocation of neurotransmitters through the cell membrane. GABA transporters are characterized in many contexts, but their spatial structure is not fully known. They are divided into four types, which differ in occurrence and role. Herein, the special attention was paid to these transporting proteins. This comprehensive review presents the current knowledge about GABA transporters. Their distribution in the body, physiological functions and possible utilization in the therapy of different diseases were fully discussed. The important structural features were described based on published data, including sequence analysis, mutagenesis studies, and comparison with known SLC6 transporters for leucine (LeuT), dopamine (DAT) and serotonin (SERT). Moreover, the most important inhibitors of GABA transporters of various basic scaffolds, diverse selectivity and potency were presented.
Highlights
Introduction γAminobutyric acid (GABA) is the primary inhibitory neurotransmitter in mammalians [1]
GAT-1 derived from rats was the first transporter, both among Gamma-aminobutyric acid (GABA) transporters and in general of all SLC6 family proteins, for which the amino acid sequence was established
Since the expression level of GAT-3 has been found to be significantly increased in Alzheimer's disease (AD)-reactive astrocytes in 5xFAD animals as well as in AD patients, GAT-3 may serve as a novel drug target for developing a therapy to treat memory deficit caused by an increased tonic current in AD patients [65]
Summary
Gamma-aminobutyric acid (GABA) transporters are heterogeneously distributed in various areas of the central nervous system (CNS) and many vital organs (Fig. 2). In the context of GABAergic neurotransmission, the primary function of all GABA transporters is to bind the extracellular GABA and transport it into the cytoplasm. The GABA concentration continues to increase until the late IPSC decay phase. Another activity of GABAergic conduction that is influenced by GABA uptake is the tonic (permanent) stimulation of GABA receptors [20]. This stimulation is a result of the constant maintenance of the low concentration of GABA in the extracellular space. The diverse distribution of different GABA transporters in the brain, in combination with their different affinities to GABA, results in an individualized response of neurons to the release of the neurotransmitter
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