Abstract
Traditionally, 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 Ca2+ changes in the nucleoplasm by coupling with Gq/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 Ca2+in situ.
Highlights
Display unique desensitization patterns, and/or exhibit distinct patterns of subcellular distribution [1,2,3,4,5]
One intracellular G-protein-coupled receptors (GPCR) found on the inner nuclear membrane (INM) is the metabotropic glutamate receptor 5. mGluR5 plays a key role in normal neurodevelopment as well as in many neurodevelopmental and neurological disorders such as Fragile X syndrome/ Autism Spectrum Disorders, anxiety, schizophrenia, drug addiction, Parkinson’s disease, dyskinesias, and chronic pain [1]
Because trafficking of GPCRs is often dictated by sequences within the cytoplasmic tail [37,38,39,40,41], we hypothesized that the mGluR5 C terminus is the domain required for INM localization
Summary
Display unique desensitization patterns, and/or exhibit distinct patterns of subcellular distribution [1,2,3,4,5]. 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 existing between the nuclear pore complex and the pore membrane, and become tethered in the INM via nucleoplasmic interactions with nuclear lamins or chromatin [22,23,24]. Many peptide-activated GPCRs use an NLS and karyopherins such as importin-1 for nuclear import after receptor activation on the cell surface [16]. Inasmuch as these receptors are not associated with the INM but rather appear within the nucleoplasm itself MGluR5 appears to use a non-canonical signal sequenceretention strategy to anchor itself on the INM where it is poised to regulate transcription [35], chromosome remodeling, and genomic integrity
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