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Reduction of glial proliferation by K+ channel blockers is mediated by changes in pHi

ASTROCYTE proliferation was studied in primary cultures of rat spinal cord by [3H]thymidine uptake, and was significantly reduced by culturing cells for 24 h in the presence of agents known to block astrocytic K+ channels: Cs+, Ba2+, 4-AP, and tetraethylammonium (TEA). To determine whether effects were mediated by changes in Vm or pHi, these parameters were studied electrophysiologically or ratiometrically, using BCECF. Of the four K+ channel blockers, only Ba2+ depolarized astrocytes significantly. However, all four K+ channel blockers resulted in an alkaline shift in pHi. Under culture conditions that altered pHi in a defined way, proliferation strongly depended on pHi, with highest rates at pH ~6.7, and growth inhibition at more acidic or alkaline conditions. These observations suggest that astrocyte proliferation is sensitive to changes in pHi, and that K+ channel blockers may exhibit their anti-proliferative effects through changes in pHi.