Constitutive and ligand‐induced nuclear localization of oxytocin receptor

Kinsey, Conan G.; Bussolati, Gianni; Bosco, Martino; Kimura, Tadashi; Pizzorno, Marie C.; Chernin, Mitchell I.; Cassoni, Paola; Novak, Josef F.

doi:10.1111/j.1582-4934.2007.00015.x

Cited by 38 publications

(39 citation statements)

References 49 publications

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“…Nuclear localization of the Oxtr on ligand binding has previously been reported in breast cancer cells and primary fibroblasts (20). In osteosarcoma cells, however, the process is constitutively active (20). Our data support these original observations but in addition, establish the precise mechanism of nuclear import.…”

Section: Discussionsupporting

confidence: 80%

“…Here, we show that the skeletal action of Oxt is mediated by and dependent on the internalization of Oxtrs and their subsequent translocation to the nucleus. Nuclear localization of the Oxtr on ligand binding has previously been reported in breast cancer cells and primary fibroblasts (20). In osteosarcoma cells, however, the process is constitutively active (20).…”

Section: Discussionmentioning

confidence: 99%

“…Human osteosarcoma and breast cancer cell lines display both cell membrane and nuclear Oxtrs (20). However, the functional significance of the nuclear localization of the Oxtr or indeed, any GPCR continues to unravel.…”

mentioning

confidence: 99%

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Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor

Benedetto

Sun

Zambonin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We report that oxytocin (Oxt) receptors (Oxtrs), on stimulation by the ligand Oxt, translocate into the nucleus of osteoblasts, implicating this process in the action of Oxt on osteoblast maturation. Sequential immunocytochemistry of intact cells or isolated nucleoplasts stripped of the outer nuclear membrane showed progressive nuclear localization of the Oxtr; this nuclear translocation was confirmed by monitoring the movement of Oxtr-EGFP as well as by immunogold labeling. Nuclear Oxtr localization was conclusively shown by Western immunoblotting and MS of nuclear lysate proteins. We found that the passage of Oxtrs into the nucleus was facilitated by successive interactions with β-arrestins (Arrbs), the small GTPase Rab5, importin-β (Kpnb1), and transportin-1 (Tnpo1). siRNA-mediated knockdown of Arrb1, Arrb2, or Tnpo1 abrogated Oxt-induced expression of the osteoblast differentiation genes osterix (Sp7), Atf4, bone sialoprotein (Ibsp), and osteocalcin (Bglap) without affecting Erk phosphorylation. Likewise and again, without affecting pErk, inhibiting Arrb recruitment by mutating Ser rich clusters of the nuclear localization signal to Ala abolished nuclear import and Oxtr-induced gene expression. These studies define a previously unidentified mechanism for Oxtr action on bone and open possibilities for direct transcriptional modulation by nuclear G protein-coupled receptors. T he oxytocin (Oxt) receptor (Oxtr), a member of the rhodopsin-type (class I) family of G protein-coupled receptors (GPCRs), responds to the neurohypophyseal hormone Oxt to stimulate lactation and social bonding (1, 2). More recently, we and others have shown that Oxt also stimulates bone formation directly by interacting with an osteoblastic Oxtr (3, 4). The genetic deletion of Oxt or Oxtr in mice thus decreases osteoblast differentiation and bone formation, causing osteopenia (5, 6). We believe that this action supports maternal skeletal remineralization after the intergenerational transfer of calcium during pregnancy and lactation (5). However, the precise mechanism through which Oxtr activation translates into increased bone formation remains unclear.Oxt binding to Oxtrs is known to activate both G protein G αi -and G αq/11 -mediated phospholipase C pathways (7). However, in common with other GPCRs, prolonged or repetitive agonist stimulation by Oxt results in Oxtr internalization through β-arrestin (Arrb). GPCR internalization can activate signaling pathways quite distinct from those activated by the same receptors resident at the cell surface. Hence, desensitization of primary G protein-dependent signaling can be followed by a second wave of Arrb-mediated signaling (8). β-Arrestins can also recruit signaling proteins that connect GPCRs to various cytoplasmic effector pathways, such as mitogen-activated protein kinase (MAPK) and protein kinase B/phosphatidylinositol-4,5-bisphosphate 3-kinase (Akt/PI3K) (9, 10). Such mechanisms can elicit delayed genomic responses.After being internalized, GPCRs are either recycled back to the plasma m...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor

Benedetto

Sun

Zambonin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The fact that immunoreactivity associated with epitope-tagged TAAR1 protein appears to be mostly intracellular already is an indication that something is special about this sequence that distinguishes it from other catecholamine receptors such as the DA D1 receptor that typically trafficks to the plasma membrane (Bunzow et al, 2001). Other GPCRs such as for vasopressin and cannabinoids have also been reported to display characteristic cytoplasmic distributions (Bohn, 2007;Fenton et al, 2007) while some, such as the oxytocin receptor (Kinsey et al, 2007) and receptors for bioactive lipoids (Gobeil et al, 2006), are associated with the nucleus.…”

Section: 2trafficking Of Vertebrate Trace Amine-associated Receptorsmentioning

confidence: 99%

Trace amine-associated receptor 1—Family archetype or iconoclast?

Grandy

2007

Pharmacology & Therapeutics

176

211

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Interest has recently been rekindled in receptors that are activated by low molecular weight, noncatecholic, biogenic amines that are typically found as trace constituents of various vertebrate and invertebrate tissues and fluids. The timing of this resurgent focus on receptors activated by the 'trace amines' (TAs) β-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of two publications that appeared in 2001 describing the cloning of a novel G protein-coupled receptor (GPCR) referred to by their discoverers as TA1 (Borowsky et al., 2001) and TAR1 (Bunzow et al., 2001). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines recombinant rodent and human TA receptors dosedependently couple to the stimulation of cAMP production. Structure-activity profiling based on this functional response has revealed that in addition to the TAs, other biologically active compounds containing a 2 carbon aliphatic side chain linking an amino group to at least one benzene ring are potent and efficacious TA receptor agonists with amphetamine, methamphetamine, 3-iodothyronamine, thyronamine, and dopamine among the most notable. Almost 100 years after the search for TA receptors began numerous TA1/TAR1-related sequences, now called Trace AmineAssociated Receptors (TAARs), have been identified in the genome of every species of vertebrate examined to date. Consequently, even though heterologously expressed TAAR1 fits the pharmacological criteria established for a bona fide TA receptor a major challenge for those working in the field is to discern the in vivo pharmacology and physiology of each purported member of this extended family of GPCRs. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast.

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“…However, human osteosarcoma (U2OS, MG63, OS15 and SaOS2), breast cancer (MCF7), and primary human fibroblastic cells (HFF) all exhibit OTR not only on the cell membrane, but also in the various nuclear compartments including the nucleolus [43]. OT induces internalization of OTR.…”

Section: Oxytocin Receptormentioning

confidence: 99%

Intranuclear Signaling Cascades Triggered by Nuclear GPCRs

Cattaneo¹,

Parisi²,

Fioretti³

et al. 2016

J Cell Signal

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G protein-couped receptors (GPCRs) play a key role on cellular membranes, where they respond to a broad array of extracellular signals such as lipids, peptides, proteins and sensory agents. Intracellular biological responses triggered by these receptors include hormone secretion, muscle contraction, cellular metabolism a tyrosine kinase receptors transactivation. Recent results indicate that GPCRs localize to and signal also at nuclear level, thus regulating distinct signaling pathways which can also result from the integration of extracellular and intracellular stimuli. Nuclear GPCRs play a central role in many cellular processes, including regulation of gene transcription, cellular proliferation, neovascularization and RNA synthesis. On nuclear membranes and in nucleoplasm are present all the downstream signal transduction components of GPCRs, including G proteins, adenylyl cyclase, and second messengers such as Ca ++ , ERKs, p38MAPK and other protein kinases. Nuclear GPCRs may be constitutively active or may be activated by ligands internalized from the extracellular space or synthesized within the cell. The translocation of membrane receptors to the nucleus could be attributed to the presence of a Nuclear Localization Signal, which is present in the eighth helix or in the third intracellular loop of a limited number of GPCRs. However, several sequence motifs that do not resemble classical Nuclear Localization Signals can promote import of GPCRs. In this review we discuss the most recent results on nuclear localization and signaling of several GPCRS.

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Constitutive and ligand‐induced nuclear localization of oxytocin receptor

Cited by 38 publications

References 49 publications

Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor

Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor

Trace amine-associated receptor 1—Family archetype or iconoclast?

Intranuclear Signaling Cascades Triggered by Nuclear GPCRs

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