Nuclear Ca2+ plays a critical role in many cellular functions although its mode (s) of regulation is unclear. This study shows that the metabotropic glutamate receptor, mGlu5, mobilizes nuclear Ca2+ independent of cytosolic Ca2+ regulation. Immunocytochemical, ultrastructural, and subcellular fractionation techniques revealed that the metabotropic glutamate receptor, mGlu5, can be localized to nuclear membranes in heterologous cells as well as midbrain and cortical neurons. Nuclear mGlu5 receptors derived from HEK cells or cortical cell types bound [3H]quisqualate. When loaded with Oregon Green BAPTA, nuclei isolated from mGlu5-expressing HEK cells responded to the addition of glutamate with rapid, oscillatory [Ca2+] elevations that were blocked by antagonist or EGTA. In contrast, carbachol-activation of endogenous muscarinic receptors led to cytoplasmic but not nuclear Ca2+ responses. Similarly, activation of mGlu5 receptors expressed on neuronal nuclei led to sustained Ca2+ oscillatory responses. These results suggest mGlu5 may mediate intranuclear signaling pathways.