Homer proteins form a physical tether linking signalingmolecules in postsynaptic densities. (a) Cultured hippocampal neurons co-immunostained for Homer2a/b (green) and the neuronal dendritic marker MAP2 (red). (b) Dendritic spines of cultured hippocampal neurons expressing exogenous GFP-Homer2 (green) and immunostained for synaptophysin (a presynapse marker; red). (c) A model of the long Homer multimer-mediated postsynaptic protein complex and Homer1a. Long Homer forms (Homers) bind to each other through their carboxy-terminal domains (probably forming a tetramer ) and to the target proteins, such as mGluR1α/5, IP3 receptor, NMDA receptor and Drebrin, to the actin cytoskeleton through their amino-terminal domains, forming a cluster at the postsynaptic density area. Homer1a, which lacks the carboxy-terminal domain, is thought to compete with long Homer forms for binding to target proteins, thus disrupting the cluster. For instance, Homers modulate mGluR-induced intracellular calcium release by linking mGluRs and IP3R: activation of mGluRs results in the phospholipase C (PLC)-mediated hydrolysis of membrane phosphatidylinositol diphosphate (PIP2) to diacylglycerol (DAG) and IP3, which activates the IP3R to release intracellular calcium. Abbreviations: AMPAR, 5-methyl-4-isoxazolepropionate receptor; CC-LZ, carboxy-terminal coiled-coil structure and leucine zipper motifs of long Homer forms; ER, endoplasmic reticulum; EVH1, the amino-terminal EVH1 domain of Homer; G, G protein; GKAP, guanylate kinase-associated protein; GRIP, glutamate receptor interacting protein; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartate receptor; VDCC, voltage-dependent Ca2+ channel.