The metabotropic glutamate receptor mGluR5, but not the closely related mGluR1, is expressed in cultured astrocytes, and this expression is up-regulated by specific growth factors. We investigated the capability and underlying mechanisms of mGluR5 to induce oscillatory responses of intracellular calcium concentration ([Ca2+]i) in cultured rat astrocytes. Single-cell [Ca2+]i recordings indicated that an mGluR-selective agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD), elicits [Ca2+]i oscillations in good agreement with the growth factor-induced up-regulation of mGluR5 in cultured astrocytes. A protein kinase C (PKC) inhibitor, bisindolylmaleimide I, converted a 1S,3R-ACPD-mediated oscillatory response into a nonoscillatory response. In addition, the PKC activator phorbol 12-myristate 13-acetate completely abolished the [Ca2+]i increase. These and other pharmacological properties of 1S,3R-ACPD-induced [Ca2+]i oscillations correlate well with those of the cloned mGluR5 characterized in heterologous expression systems. Furthermore, the potential involvement of protein phosphatases in [Ca2+]i oscillations is suggested. The present study demonstrates that mGluR5 is capable of inducing [Ca2+]i oscillations in cultured astrocytes and that phosphorylation/dephosphorylation of mGluR5 is critical in [Ca2+]i oscillations, analogous to the cloned mGluR5 expressed in heterologous cell lines.