Intricacies of GABA(A) Receptor Function: The Critical Role of the β3 Subunit in Norm and Pathology

Neuronal intracellular chloride ([Cl(−)](i)) is a key determinant in γ-aminobutyric acid type A (GABA)ergic signaling. γ-Aminobutyric acid type A receptors (GABA(A)Rs) mediate both inhibitory and excitatory neurotransmission, as the passive fluxes of Cl(−) and HCO(3)(−) via pores can be reversed by changes in the transmembrane concentration gradient of Cl(−). The cation–chloride co-transporters (CCCs) are the primary systems for maintaining [Cl(−)](i) homeostasis. However, despite extensive electrophysiological data obtained in vitro that are supported by a wide range of molecular biological studies on the expression patterns and properties of CCCs, the presence of ontogenetic changes in [Cl(−)](i)—along with the consequent shift in GABA reversal potential—remain a subject of debate. Recent studies showed that the β3 subunit possesses properties of the P-type ATPase that participates in the ATP-consuming movement of Cl(−) via the receptor. Moreover, row studies have demonstrated that the β3 subunit is a key player in GABA(A)R performance and in the appearance of serious neurological disorders. In this review, we discuss the properties and driving forces of CCCs and Cl(−), HCO(3)(−)ATPase in the maintenance of [Cl(−)](i) homeostasis after changes in upcoming GABA(A)R function. Moreover, we discuss the contribution of the β3 subunit in the manifestation of epilepsy, autism, and other syndromes.