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

Neuronal intracellular chloride ([Cl]) is a key determinant in γ-aminobutyric acid type A (GABA)ergic signaling. γ-Aminobutyric acid type A receptors (GABARs) mediate both inhibitory and excitatory neurotransmission, as the passive fluxes of Cl and HCO 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] 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]-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 GABAR performance and in the appearance of serious neurological disorders. In this review, we discuss the properties and driving forces of CCCs and Cl, HCOATPase in the maintenance of [Cl] homeostasis after changes in upcoming GABAR function. Moreover, we discuss the contribution of the β3 subunit in the manifestation of epilepsy, autism, and other syndromes.