Astrocytes participate in signaling via Ca2+ transients that spread from cell to cell across a multicellular syncytium. The effect, if any, of these Ca2+ waves on the transcription of Ca2+/cAMP-regulatory element binding protein (CREB)-dependent genes is not known. We report here that, unlike neurons, increasing intracellular Ca2+ in cultured mouse cortical astrocytes failed to activate CREB-dependent transcription, even though CREB was phosphorylated at serine 133. In contrast, both CREB phosphorylation and CREB-dependent transcription were robustly stimulated by increasing cAMP. The failure of Ca2+-activated transcription in astrocytes was correlated with the absence of CaMKIV, a Ca2+-dependent protein kinase required for Ca2+-stimulated gene transcription in neurons. The inability of Ca2+ to signal via CaMKIV may insulate CREB-dependent gene transcription in astrocytes from activation by Ca2+ waves. © 2008 Wiley-Liss, Inc.