Topic: neuronal chloride homeostasis

KCC2 is a neuronal-specific chloride extruder that acts to maintain a low intraneuronal chloride concentration, which is critical for fast synaptic inhibition through the GABAA receptor channels. In both humans and mice, KCC2 encoding gene is translated into two isoforms (KCC2a and KCC2b) that differ in their N-terminal domain. While KCC2b is strongly upregulated after birth, KCC2a remains very weakly expressed even in mature neurons. Despite its low expression, KCC2a has been shown to be essential for respiratory behaviour at birth, but the specific function of KCC2a in mature neurons has not

Neuronal chloride homeostasis is determined by KCC2 and NKCC1 transporters responsible for chloride efflux and influx. KCC2 internalization and increased NKCC1 surface expression leads to a pathological state by accumulation of chloride in neurons. Molecules designed to reduce intra-neuronal chloride levels - by stabilizing KCC2 or destabilizing NKCC1 at the membrane - represent promising therapeutic strategies for diseases in which inhibition is impaired. The WNK/SPAK kinase pathway, by regulating the phosphorylation and membrane stability of both NKCC1 and KCC2, constitutes a new target of i