Pharmacological inhibition of cation-chloride cotransporters for neurological diseases.

Abstract

γ-Aminobutyric acid (GABA) is a major neurotransmitter and plays important roles in both the developing and mature central nervous system (CNS). One way that GABA can act is by binding to fast, ionotropic GABAA receptors in neurons. The binding of GABA to GABAA receptors causes a conformational change that opens ion channels, allowing the passage of Cl– ions. In mature adults, intracellular Cl– concentration [Cl–]i) is low, and the opening of these ion channels triggers influx of Cl– ions, causing hyperpolarization and neuronal inhibition (Blaesse, 2009). However, in the developing nervous system, [Cl–]i is high, and the binding of GABA to GABAA receptors induces a depolarizing excitatory response (Figure 1). This leads to the stimulation of voltage-dependent Ca2+ channels, which is important for proper neuronal proliferation and differentiation in their circuitry development. Gradual changes in [Cl–]i during development, known as the “GABA shift”, determine the strength and polarity of GABA-mediated activity. The precise regulation of [Cl–]i is determined by two major cation-chloride cotransporters (CCCs), the inwardly directed Na-K-2Cl cotransporter (NKCC1) and the Cl– extruding K-Cl cotransporter (KCC2) (Blaesse, 2009). NKCC1 is expressed in a wide range of neurons and glia, but especially in embryonic ventricular zones, which suggests an important role in neuronal proliferation. KCC2 is located in plasma membrane of both somata and dendrites of neurons in various brain regions, including cortical pyramidal neurons, thalamic relay cells, and auditory brainstem neurons (Blaesse, 2009). In embryonic and early postnatal life, neurons show high expression of NKCC1and low expression of KCC2 (Figure 1). NKCC1 functions in Cl– influx and raises the [Cl–]i during the early development of the CNS, which enables GABAA receptor-mediated neuronal depolarization and excitation. NKCC1 expression rapidly decreases during the first year of life to levels common in an adult, while KCC2 expression rises (Dzhala et al., 2005). KCC2 functions in Cl– efflux and lowering [Cl–]i, which leads to the dominance of GABAA receptor-mediated hyperpolarization and inhibition response in the maturing brain (Figure 1).