Abstract
Intracellular chloride concentrations ([Cl−]i) in CNS neurons are regulated by several transporters to be lower than that expected from passive distribution. Among these transporters, ATP-dependent chloride pump acts as an outwardly directed and primarily active chloride transporter requiring phosphatidylinositol 4-monophosphate (PI4P) for its maximal activity. A decrease in plasma membrane PI4P level reduces the pump activity resulting in an increase in neuronal [Cl−]i. Such cases can be observed when PI turnover was accelerated with poor supplies of PI substrates, or plasma membrane type II PI 4-kinase (PI4KII) was inhibited by pathophysiological concentrations of amyloid-beta proteins of Alzheimer disease. Neuronal [Cl−]i increases from 6 mM to around 30 mM, and this enhances glutamate toxicity at its physiological concentration resulting in neuronal cell death. Mechanisms of this enhancement are partially explained by inhibition of chloride-sensitive activity of PDK2 by higher [Cl−]i, and by resulting decreases in cell survival molecule phospho-Akt Ser473 level. Regulation of pathological changes in neuronal [Cl−]i is protective against the enhancement of glutamate toxicity. Supplement of substrates for PI or PI4P production, cyclic GMP as PI4K activator, GABAc receptor agonists and short peptides blocking amyloid-beta-induced inhibition of PI4K, reversed the inhibition of chloride pump activity as well as the increases in neuronal [Cl−]i, and finally recover the cell viability. Regulation of [Cl−]i thus seems to be essential for neuronal cell survival. [J Physiol Sci. 2007;57 Suppl:S21]
