Sequences within the C Terminus of the Metabotropic Glutamate Receptor 5 (mGluR5) Are Responsible for Inner Nuclear Membrane Localization

Jong, Yuh-Jiin I.; Harmon, Steven K.; Kumar, Vikas; O’Malley, Karen L.

doi:10.1074/jbc.m116.757724

Cited by 34 publications

(37 citation statements)

References 77 publications

(126 reference statements)

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“…As the human B1R lacks typical NLS motifs, this would argue against an influential role for NLS in the nuclear import of this receptor. Nonetheless, other receptor intracellular domains could be involved as has been recently documented for the metabotropic glutamate receptor 5 (Sergin, Jong, Harmon, Kumar, & O’Malley, ) and the vasoactive intestinal peptide VPAC1R (Yu et al, ); post‐translational modifications of GPCRs may, or may not be, required for nuclear import. The existence of mutated forms of B1R would be one attractive hypothesis to account for the presence of nuclear B1R in TNBC.…”

Section: Discussionmentioning

confidence: 94%

Antitumor activity of cell‐penetrant kinin B1 receptor antagonists in human triple‐negative breast cancer cells

Dubuc

Savard

Bovenzi

et al. 2018

Journal Cellular Physiology

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High nuclear expression of G protein-coupled receptors, including kinin B1 receptors (B1R), has been observed in several human cancers, but the clinical significance of this is unknown. We put forward the hypothesis that these "nuclearized" kinin B1R contribute to tumorigenicity and can be a new target in anticancer strategies. Our initial immunostaining and ultrastructural electron microscopy analyses demonstrated high B1R expression predominantly located at internal/nuclear compartments in the MDA-MB-231 triple-negative breast cancer (TNBC) cell line as well as in clinical samples of patients with TNBC. On the basis of these findings, in the present study, we evaluated the anticancer therapeutic potential of newly identified, cell-permeable B1R antagonists in MDA-MB-231 cells (ligand-receptor binding/activity assays and LC-MS/MS analyses). We found that these compounds (SSR240612, NG67, and N2000) were more toxic to MDA-MB-231 cells in comparison with low- or non-B1R expressing MCF-10A normal human mammary epithelial cells and COS-1 cells, respectively (clonogenic, MTT proliferative/cytocidal assays, and fluorescence-activated cell-sorting (FACS)-based apoptosis analyses). By comparison, the peptide B1R antagonist R954 unable to cross cell membrane failed to produce anticancer effects. Furthermore, the putative mechanisms underlying the anticancer activities of cell-penetrant B1R antagonists were assessed by analyzing cell cycle regulation and signaling molecules related to cell survival and apoptosis (FACS and western blot). Finally, drug combination experiments showed that cell-penetrant B1R antagonists can cooperate with suboptimal doses of chemotherapeutic agents (doxorubicin and paclitaxel) to promote TNBC death. This study provides evidence on the potential value of internally acting kinin B1R antagonists in averting growth of breast cancer.

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Section: Discussionmentioning

confidence: 94%

Antitumor activity of cell‐penetrant kinin B1 receptor antagonists in human triple‐negative breast cancer cells

Dubuc

Savard

Bovenzi

et al. 2018

Journal Cellular Physiology

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“…Not all nuclear GPCRs contain canonical NLS sequences. Some like the metabotropic glutamate receptor, mGlu 5 , contain previously unidentified targeting sequences that are critical for the receptor's nuclear localization (Sergin et al ., ). Although the transport proteins responsible for this movement have not been identified, the sequences themselves are necessary and sufficient for mGlu 5 nuclear localization (Sergin et al ., ).…”

Section: Trafficking Of Nuclear Gpcrsmentioning

confidence: 97%

GPCR signalling from within the cell

Jong

Harmon

O’Malley

2017

British J Pharmacology

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“…Left, proposed model of mGlu 5 receptors trafficking in neurons in which >90% of mGlu 5 traffics through the Golgi (27). Subsequently, 15–40% goes to the cell surface where it undergoes a cycle of constitutive endocytosis and recycling (27, 122). Alternatively, 60–85% of mGlu 5 is retrogradely trafficked back to the endoplasmic reticulum (ER) and then, via lateral diffusion (dotted blue line), reaches the nuclear membrane (27, 123).…”

Section: Figmentioning

confidence: 99%

“…Thus there is no one preferred pathway that is involved in this process nor do all nuclear GPCRs contain canonical NLS sequences. Some like mGlu 5 receptors contain unidentified targeting sequences which are critical for the receptor’s nuclear localization (27). Interestingly, some receptors trafficked from the cell surface are not associated with nuclear membranes but rather appear within the nucleoplasm itself.…”

Section: Introductionmentioning

confidence: 99%

“…The diffusion-retention model suggests that proteins synthesized in the ER or retrogradely transported there, rapidly diffuse along the outer nuclear membrane before passing through peripheral channels located between the nuclear pore complex and the pore membrane to become tethered on the inner nuclear membrane via interactions with nuclear lamins or chromatin (35, 36). For example, the mGlu 5 nuclear trafficking motif interacts with chromatin via a basic region (pI >9.8) which may promote its nuclear retention (27). Most recently, it was reported that VPAC1, a class B GPCR shared by pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), was trafficked to the nuclear membrane via palmitoylation of its most N-terminal cysteine (Cys37) in the extracellular domain (37).…”

Section: Introductionmentioning

confidence: 99%

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Intracellular GPCRs Play Key Roles in Synaptic Plasticity

Jong

Harmon

O’Malley

2018

ACS Chem. Neurosci.

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The trillions of synaptic connections within the human brain are shaped by experience and neuronal activity both of which underlie synaptic plasticity and ultimately learning and memory. G protein-coupled receptors (GPCRs) play key roles in synaptic plasticity by strengthening or weakening synapses and/or shaping dendritic spines. While most studies of synaptic plasticity have focused on cell surface receptors and their downstream signaling partners, emerging data point to a critical new role for the very same receptors to signal from inside the cell. Intracellular receptors have been localized to nuclear, endoplasmic reticulum, lysosomes and mitochondria. From these intracellular positions, such receptors may couple to different signaling systems, display unique desensitization patterns and/or show distinct patterns of subcellular distribution. Intracellular GPCRs can be activated at the cell surface, endocytosed and transported to an intracellular site or simply activated in situ by de novo ligand synthesis, diffusion of permeable ligands or active transport of nonpermeable ligands. Current findings reinforce the notion that intracellular GPCRs play a dynamic role in synaptic plasticity and learning and memory. As new intracellular GPCR roles are defined, the need to selectively tailor agonists and/or antagonists to both intracellular and cell surface receptors may lead to the development of more effective therapeutic tools.

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Sequences within the C Terminus of the Metabotropic Glutamate Receptor 5 (mGluR5) Are Responsible for Inner Nuclear Membrane Localization

Cited by 34 publications

References 77 publications

Antitumor activity of cell‐penetrant kinin B1 receptor antagonists in human triple‐negative breast cancer cells

Antitumor activity of cell‐penetrant kinin B1 receptor antagonists in human triple‐negative breast cancer cells

GPCR signalling from within the cell

Intracellular GPCRs Play Key Roles in Synaptic Plasticity

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