Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, are thought to signal through the phospholipase and inositol (1,4,5)-trisphosphate receptor system, or through the adenylyl cyclase and protein kinase C system. Rong et al. have recently identified a new phosphoinositide (PI) 3-kinase enhancer (PIKE-L) that links group I mGlu receptors (mGluRI) to PI 3-kinase through Homer proteins, adaptors that bind mGluRI. mGluRI agonists enhanced mGluRI-Homer-PIKE-L complex formation, leading to activation of PI 3-kinase and inhibition of staurosporine-induced neuronal apoptosis. These results reveal a novel anti-apoptotic signaling mechanism that involves formation of an mGluRI signaling complex.