Group 1 metabotropic glutamate receptors (mGluRs) activate PI turnover and thereby trigger intracellular calcium release. Previously, we demonstrated that mGluRs form natural complexes with members of a family of Homer-related synaptic proteins. Here, we present evidence that Homer proteins form a physical tether linking mGluRs with the inositol trisphosphate receptors (IP3R). A novel proline-rich 'Homer ligand' (PPXXFr) is identified in group 1 mGluRs and IP3R, and these receptors coimmunoprecipitate as a complex with Homer from brain. Expression of the lEG form of Homer, which lacks the ability to cross-link, modulates mGluR- induced intracellular calcium release. These studies identify a novel mechanism in calcium signaling and provide evidence that an lEG, whose expression is driven by synaptic activity, can directly modify a specific synaptic function.