Edited by Roger J. ColbranTraditionally, G-protein-coupled receptors (GPCR) are thought to be located on the cell surface where they transmit extracellular signals to the cytoplasm. However, recent studies indicate that some GPCRs are also localized to various subcellular compartments such as the nucleus where they appear required for various biological functions. For example, the metabotropic glutamate receptor 5 (mGluR5) is concentrated at the inner nuclear membrane (INM) where it mediates Ca 2؉ changes in the nucleoplasm by coupling with G q/11 . Here, we identified a region within the C-terminal domain (amino acids 852-876) that is necessary and sufficient for INM localization of the receptor. Because these sequences do not correspond to known nuclear localization signal motifs, they represent a new motif for INM trafficking. mGluR5 is also trafficked to the plasma membrane where it undergoes re-cycling/degradation in a separate receptor pool, one that does not interact with the nuclear mGluR5 pool. Finally, our data suggest that once at the INM, mGluR5 is stably retained via interactions with chromatin. Thus, mGluR5 is perfectly positioned to regulate nucleoplasmic Ca 2؉ in situ.From their position on the cell surface, G-protein-coupled receptors (GPCRs) 3 can transform external stimuli into a broad range of signaling pathways within the cell. A mounting body of evidence indicates that many GPCRs are also localized inside the cell where they may couple to different signaling systems, display unique desensitization patterns, and/or exhibit distinct patterns of subcellular distribution (1-5). For example, GPCRs have been found on mitochondria (6), endoplasmic reticulum (ER) membranes (7), lysosomes (8, 9), and on nuclear membranes (10 -12). Certain GPCRs are even found within the nucleoplasm on nuclear bodies and/or nuclear invaginations (13-16). Although many intracellular GPCRs are activated at the cell surface and subsequently trafficked to their intracellular site, others can be activated at their subcellular location via so-called intracrine ligands that can enter cells via diffusion or be made in situ, endocytosed, and/or transported through channels or pores (12,17,18). Intracellular GPCRs can also function independently governing processes such as synaptic plasticity (19), myocyte contraction (15), and angiogenesis (16). Collectively, the present findings reinforce the notion that intracellular GPCRs play a dynamic role in generating and shaping intracellular signaling pathways.As many GPCRs are on or in the nucleus, the question arises as to how they get there. Various possibilities exist to transfer membrane proteins from the outer to the inner nuclear membrane (ONM and INM), including vesicle fusion, membrane rupture, and channel-mediated pathways. Most prominently, a diffusion-retention model has been proposed for many INM proteins (e.g. lamin B receptor (LBR)) (20,21). This model suggests that proteins synthesized in the ER rapidly diffuse laterally in the ONM, pass through peripheral channels ex...