Neuronal signaling relies on ion fluxes through membrane-bound channels. Such fluxes are allowed due to the transmembrane ionic gradients created and maintained by membrane transporters. The neuronal gradient for chloride, an anion mediating most of the inhibition in the mature CNS, is the result of activity of two chloride transporters working in opposite directions, NKCC1 moving chloride in and KCC2 moving chloride out of the cell. The KCC2 function may be both up- and down-regulated through a number of mechanisms which allow for the fine-tune adaptation to a varying transporting load which mostly depends on chloride influx through both synaptic and extrasynaptic inhibitory chloride-permeable ion channels such as GABAA- and glycine-receptors.
Besides intraneuronal factors affecting KCC2 function and, thus, the chloride gradient, there is a number of extra-neuronal factors suggested to have a great influence over the distribution of chloride across the neuronal membrane. The very recent experimental findings point to the extracellular matrix as an important player in regulation of intracellular chloride. It has been claimed that large anion groups located within the extracellular matrix set the chloride gradient due to the Gibbs-Donnan effect, thus, effectively sidelining KCC2 as a major contributor to the neuronal chloride homeostasis. However, our own experimental findings concerning chloride homeostasis in anterior hypothalamic neurons suggest quite a different mechanism of involvement of the extracellular matrix.