Recent evidence suggests that astrocytes do not serve a mere buffering function, but exhibit complex signaling pathways, disturbance of which contributes significantly to the pathophysiology of CNS diseases. Little is known regarding the intracellular signaling pathways in the specialized optic nerve head astrocytes (ONHAs), the major glia cell type in non-myelinated optic nerve head. Here we show the differential subcellular expression of intracellular Ca(2+) channels in ONHAs. Expression of type 1 and type 3 inositol-1-4-5,-trisphosphate receptors (IP3Rs) in the endoplasmic reticulum and type 2 IP3Rs in the nuclear envelope causes differential Ca(2+) release from intracellular stores in nuclear vs. cytosolic compartments. Our study identifies differential distribution and activity of Ca(2+) channels as molecular substrate and mechanism by which astrocytes independently regulate Ca(2+) transients in both cytoplasm and nucleoplasm, thereby controlling genomic and non-genomic cellular signaling, respectively. This provides excellent targets for therapeutics restoring pathological disturbances of intracellular Ca(2+) signaling present in glaucoma and other neurodegenerative disorders with astrocyte involvement.