Abstract
Neuronal intracellular chloride ([Cl−]i) is a key determinant in γ-aminobutyric acid type A (GABA)ergic signaling. γ-Aminobutyric acid type A receptors (GABAARs) mediate both inhibitory and excitatory neurotransmission, as the passive fluxes of Cl− and HCO3− 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 GABAAR performance and in the appearance of serious neurological disorders. In this review, we discuss the properties and driving forces of CCCs and Cl−, HCO3−ATPase in the maintenance of [Cl−]i homeostasis after changes in upcoming GABAAR function. Moreover, we discuss the contribution of the β3 subunit in the manifestation of epilepsy, autism, and other syndromes.
Highlights
Intracellular chloride ([Cl− ]i ) and bicarbonate ([HCO3 − ]i ) concentrations are pivotal parameters that control neuronal inhibition and excitation; their effect depends on neuronal specialization and the level of development [1,2,3,4]. γ-Aminobutyric acid type A receptors (GABAA Rs) are ionotropic receptors that mediate inhibitory or excitatory neurotransmission, as the net flux of Cl− and HCO3 − via pores can be reversed by modest changes in the transmembrane concentration gradient of Cl− [5,6,7]
Mice lacking the β3 subunits exhibit thalamic disinhibition, a major reduction in GABAA R expression, and seizures that are associated with learning and memory deficits, poor motor skills on a repetitive task, hyperactivity, and a disturbed rest–activity cycle [120]—all features characteristic of children affected by this neurological disorder [110,111,112,113,114,116]
Research data on the properties of GABAA Rs highlight that the β3 subunit is an independent structure that can singly form an ion pore; importantly, it is a key polypeptide that facilitates inhibitory neurotransmission
Summary
Intracellular chloride ([Cl− ]i ) and bicarbonate ([HCO3 − ]i ) concentrations are pivotal parameters that control neuronal inhibition and excitation; their effect depends on neuronal specialization and the level of development [1,2,3,4]. γ-Aminobutyric acid type A receptors (GABAA Rs) are ionotropic receptors that mediate inhibitory or excitatory neurotransmission, as the net flux of Cl− and HCO3 − via pores can be reversed by modest changes in the transmembrane concentration gradient of Cl− [5,6,7]. Under certain circumstances (for example, massive activation), GABAA ergic signaling can be switched from fast hyperpolarization to long-term depolarization of the EM [12,13,14] Such paroxysmal depolarizing shifts in the EM during seizures induce Cl− accumulation or the efflux of HCO3 − through GABAA R channels [15,16]. Functional GABAA Rs are heteropentameric, consisting of five individual subunits encoded by 19 genes that have been characterized and grouped according to their amino acid similarity and named α1-6, β1-3, γ1-3, δ, ε, θ, π, and p1-3 [26,27] These GABAA R subunits are assembled to have a high level of heterogeneity with the general stoichiometry of the 2α, 2β, and 1γ subunits [28]. We consider the exceptional role of the β3 subunit in the manifestation of some neurological disorders
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