The role of Na-K-Cl co-transporter in cerebral ischemia.

The electroneutral Na-K-Cl co-transporter (NKCC) protein transports Na(+), K(+) and Cl(-) into cells under physiological conditions with a stoichiometry of 1Na(+) :1K(+) :2Cl(-). NKCC is characteristically inhibited by the sulfamoylbenzoic acid "loop'' diuretics, such as bumetanide and furosemide. To date, only two distinct isoforms, NKCC1 and NKCC2, have been identified. NKCC1 has a broad tissue distribution, while the NKCC2 isoform is only found in vertebrate kidney. NKCC serves multiple functions, including ion and fluid movements in secreting or reabsorbing epithelia and cell volume regulation. However, understanding the role of NKCC1 in the central nervous system has just begun. NKCC1 protein is expressed in neurons throughout the brain. Dendritic localization of NKCC1 is found in both pyramidal and non-pyramidal neurons. NKCC1 is important in the maintenance of intracellular Cl(-) in neurons and contributes to GABA-mediated depolarization in immature neurons. Thus, NKCC1 may affect neuronal excitability through regulation of intracellular Cl(-) concentration. Expression of NKCC1 protein has also been found in astrocytes and oligodendrocytes. In addition to its role in the accumulation of Cl(-), NKCC1 may also contribute to K(+) clearance and maintenance of intracellular Na(+) in glia. Our recent studies suggest that NKCC1 activation leads to high K(+) induced astrocyte swelling and glutamate release, as well as neuronal Na(+) , and Cl(-) influx during acute excitotoxicity. Inhibition of NKCC1 activity significantly reduces infarct volume and cerebral edema following cerebral focal ischemia.