Introduction table 1 Astrocytes, the major glial cell type of the central ner vous system, are known to play a major role Inhibitors,Modulators,Libraries in normal brain signaling and their dysfunction has been shown to be critically involved in the pathogenesis of several human CNS disorders, including epilepsy. One of the most important physiological functions of astrocytes is their ability to control ionic homeostasis, in particular the extracellular concentration of potassium, which influences neuronal excitability. The in wardly rectifying potassium channel 4. 1 has been identified as a key player among the potassium channels expressed in astrocytes responsible for spatial buffering. Conditional knock out of Kir4. 1 has been shown to lead to inhibition of potassium and glutamate uptake, hyperexcitability, and seizures.

Mutations Inhibitors,Modulators,Libraries in the human Kir4. 1 gene, KCNJ10, are associated with epilepsy and a compromised glial potassium spatial buffering has been suggested to underlie the epilepsy phenotype. In addition, alterations in expression, localization, and function of Kir4. 1, have been reported in astrocytes in a number of neurological disorders, including temporal lobe epilepsy and malignant gliomas. In tissue specimens obtained from patients with epilepsy, both electrophysiological and molecular studies suggest that impaired potas sium Inhibitors,Modulators,Libraries buffering and enhanced seizure susceptibility may result from Inhibitors,Modulators,Libraries reduced expression of Kir4. 1 chan nels. In the fluid percussion injury model in rat, a chronic dysfunction of Kir channels in the epileptic focus has been reported.

In Inhibitors,Modulators,Libraries case of astrocytic tumors, which are often associated with seizure development, mislocalization, andor redistribution of Kir4. 1, as well as changes in the expression related to the ma lignancy grade, have been reported. In addition, attention has been focused on the role of Kir channels as critical regulators of cell division, suggesting that a loss of functional Kir4. 1 may underlie the re entry of glial cells into the cell cycle supporting gliosis and tumor development. Al though these observations support an important role for astrocytic Kir4. 1, it remains still unclear whether the changes in Kir4. 1 expression represent the cause or the consequence of epilepsy and the mechanism underlying the regulation of the expression of Kir4. 1 is still matter of discussion.

It has been shown that albumin uptake into astrocytes, mediated by trans forming growth factor B receptors, produces a downregulation of Kir4. 1 in these cells. In spinal cord injury, the downregulation of Kir4. 1 has been suggested to be dependent on the nuclear es trogen receptor signaling. Moreover, recently, Kir4. 1 expression has been suggested to be influ enced by changes in the extracellular environment of inflammatory cytokines, such as interleukin 1B.

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