: During the previous application cycle we showed profound biophysical differences between dividing astrocytes and their differentiated counterparts. Dividing astrocytes show a positive shift in resting potential, which is caused by a loss of Kir currents and activation of outwardly rectifying currents, largely mediated by Kv1.5 channels. We have shown that the latter become reversibly activated during the cell cycle by Src -nediated tyrosine phosphorylation. Moreover, we have shown that this developmental program is recapitulated in astrocytes after injury (gliosis). Astrocyte differentiation correlates with down-regulation of Kv1 .5 and upregulation of Kir currents, associated with a negative shift in resting potential and much enhanced resting K+ conductance. Differentiation is retarded when Kir channels are inhibited. The molecular identity and regulation of Kir channels in astrocytes is largely unknown. It is imperative to fill this void since astrocytic Kir channels are believed to mediate K+ buffering in the nervous system through diffusional uptake of excess K+. It is the principal objective of this application to determine which channels mediate Kir currents in astrocytes, to determine their regulation, and examine their role in cell differentiation. We are now proposing to use Kir specific antibodies to examine tissue sections of rat and human brain/spinal cord and obtain Western Blots from these tissues to identify Kir proteins specifically expressed in astrocytes. We will correlate Kir expression with cell proliferation and cell differentiation. Anti-sense oligonucleotides will be used to selectively eliminate subsets of Kir channels to biophysically examine their contribution to astrocytic K+ conductance. Moreover, biochemical and electrophysiological approaches will be used to examine how physiologically relevant changes in the astrocytic environment may directly alter expression and function of Kir channels in astrocytes. These focusing specifically on the role of pH and thosphorylation through kinases involved in the astrocytic cell cycle.
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