71 results found
Nikolopoulou E, Papacleovoulou G, Jean-Alphonse F, et al., 2014, Arachidonic acid-dependent gene regulation during preadipocyte differentiation controls adipocyte potential, Journal of Lipid Research, Vol: 55, Pages: 2479-2490, ISSN: 0022-2275
Arachidonic acid (AA) is a major PUFA that has been implicated in the regulation of adipogenesis. We examined the effect of a short exposure to AA at different stages of 3T3-L1 adipocyte differentiation. AA caused the upregulation of fatty acid binding protein 4 (FABP4/aP2) following 24 h of differentiation. This was mediated by the prostaglandin F2α (PGF2α), as inhibition of cyclooxygenases or PGF2α receptor signaling counteracted the AA-mediated aP2 induction. In addition, calcium, protein kinase C, and ERK are all key elements of the pathway through which AA induces the expression of aP2. We also show that treatment with AA during the first 24 h of differentiation upregulates the expression of the transcription factor Fos-related antigen 1 (Fra-1) via the same pathway. Finally, treatment with AA for 24 h at the beginning of the adipocyte differentiation is sufficient to inhibit the late stages of adipogenesis through a Fra-1-dependent pathway, as Fra-1 knockdown rescued adipogenesis. Our data show that AA is able to program the differentiation potential of preadipocytes by regulating gene expression at the early stages of adipogenesis.
Psichas A, Sleeth ML, Murphy KG, et al., 2014, The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents, International Journal of Obesity, Vol: 39, Pages: 424-429, ISSN: 1476-5497
Kim SH, Blanks A, Thornton S, et al., 2014, Oxytocin Receptor Antagonist, Atosiban, Drives Proinflammatory Effects in Human Amnion Via G(ai) Signaling., 61st Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI), Publisher: SAGE PUBLICATIONS INC, Pages: 111A-111A, ISSN: 1933-7191
Jean-Alphonse F, Bowersox S, Chen S, et al., 2013, Spatially restricted G protein-coupled receptor signaling via divergent endocytic compartments, Journal of Biological Chemistry, Vol: 289, ISSN: 1083-351X
Postendocytic sorting of G protein-coupled receptors (GPCRs) is driven by their interactions between highly diverse receptor sequence motifs with their interacting proteins, such as postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), zonula occludens-1 protein (zo-1) (PDZ) domain proteins. However, whether these diverse interactions provide an underlying functional specificity, in addition to driving sorting, is unknown. Here we identify GPCRs that recycle via distinct PDZ ligand/PDZ protein pairs that exploit their recycling machinery primarily for targeted endosomal localization and signaling specificity. The luteinizing hormone receptor (LHR) and β2-adrenergic receptor (B2AR), two GPCRs sorted to the regulated recycling pathway, underwent divergent trafficking to distinct endosomal compartments. Unlike B2AR, which traffics to early endosomes (EE), LHR internalizes to distinct pre-early endosomes (pre-EEs) for its recycling. Pre-EE localization required interactions of the LHR C-terminal tail with the PDZ protein GAIP-interacting protein C terminus, inhibiting its traffic to EEs. Rerouting the LHR to EEs, or EE-localized GPCRs to pre-EEs, spatially reprograms MAPK signaling. Furthermore, LHR-mediated activation of MAPK signaling requires internalization and is maintained upon loss of the EE compartment. We propose that combinatorial specificity between GPCR sorting sequences and interacting proteins dictates an unprecedented spatiotemporal control in GPCR signal activity.
Kandola MK, Sykes L, Lee YS, et al., 2013, EP2 Receptor Activates Dual G Protein Signaling Pathways that Mediate Contrasting Proinflammatory and Relaxatory Responses in Term Pregnant Human Myometrium, Endocrinology, Vol: Epub ahead of print
Prostaglandin (PG) E2 (PGE2) plays a central role in the regulation of smooth muscle contractions. Classically, PGE2 stimulates contractions via EP1 and EP3 receptors, whereas EP2 and EP4 maintain quiescence. Labor involves a change from myometrial quiescence to contractions with a shift from anti- to proinflammatory pathways. EP2, a Gαs-coupled receptor, is known to mediate its actions via cAMP signaling. However, we have recently shown that EP2 also activates the proinflammatory PG G/H synthase-2 (PGHS-2). Here, we identify the mechanism underlying the ability of EP2 to maintain uterine quiescence and activate a proinflammatory/prolabor response in term-pregnant human myometrium. Human myometrial biopsies for in vivo and in vitro studies were taken at cesarean section at term, before or after the onset of labor. Activation of EP2 increased intracellular levels of cAMP and reduced contractility. Contrastingly, EP2 stimulation increased levels of PGHS-2, PG synthase mPGES-1, and PGE2. This was entirely dependent on EP2-mediated activation of calcium signaling. Both calcium signaling and up-regulation of PGHS-2 were insensitive to the Gαi inhibitor pertussis toxin but inhibited by siRNA knockdown of Gαq/11. There were no differences in EP2 mRNA or protein levels between upper or lower segment myometrium or between pre- and postlabor myometrium. However, in myocytes taken after the onset of labor, cAMP signaling was markedly attenuated, whereas activation of calcium and PGHS-2 was preserved. Overall, the dual coupling of EP2 to Gαs-cAMP and Gαq/11-calcium pathways underlies its ability to mediate contrasting functions in term pregnancy and the “switching” to a prolabor receptor.
Jonas KC, Rivero-Mueller A, Huhtaniemi IT, et al., 2013, G Protein-Coupled Receptor Transactivation: From Molecules to Mice, RECEPTOR-RECEPTOR INTERACTIONS, Vol: 117, Pages: 433-450, ISSN: 0091-679X
Rivero-Muller A, Jonas KC, Hanyaloglu AC, et al., 2013, Di/Oligomerization of GPCRs-Mechanisms and Functional Significance, OLIGOMERIZATION IN HEALTH AND DISEASE, Vol: 117, Pages: 163-185, ISSN: 1877-1173
Arulkumaran S, Kandola MK, Hoffman B, et al., 2012, The Roles of Prostaglandin EP 1 and 3 Receptors in the Control of Human Myometrial Contractility, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 97, Pages: 489-498, ISSN: 0021-972X
Arulkumaran S, Kandola MK, Hoffman B, et al., 2012, The Roles of Prostaglandin EP 1 and 3 Receptors in the Control of Human Myometrial Contractility., J Clin Endocrinol Metab, Vol: 97, Pages: 489-498
Al-Sabbagh M, Fusi L, Higham J, et al., 2011, NADPH Oxidase-Derived Reactive Oxygen Species Mediate Decidualization of Human Endometrial Stromal Cells in Response to Cyclic AMP Signaling, REPRODUCTIVE SCIENCES, Vol: 18, Pages: 162A-162A, ISSN: 1933-7191
Al-Sabbagh M, Fusi L, Higham J, et al., 2011, NADPH Oxidase-Derived Reactive Oxygen Species Mediate Decidualization of Human Endometrial Stromal Cells in Response to Cyclic AMP Signaling, ENDOCRINOLOGY, Vol: 152, Pages: 730-740, ISSN: 0013-7227
Al-Sabbagh M, Fusi L, Higham J, et al., 2011, NADPH oxidase-derived reactive oxygen species mediate decidualization of human endometrial stromal cells in response to cyclic AMP signaling., Endocrinology, Vol: 152, Pages: 730-740
Jean-Alphonse F, Hanyaloglu AC, 2010, Regulation of GPCR signal networks via membrane trafficking, Molecular and Cellular Endocrinology, Vol: 331, Pages: 205-214
-protein-coupled receptors (GPCRs) are a superfamily of cell surface signaling proteins that act as central molecular activators and integrators in all endocrine systems. Membrane trafficking of GPCRs is a fundamental process in shaping extensive signaling networks activated by these receptors. Mounting evidence has identified an increasingly complex network of pathways and protein interactions that a GPCR can traverse and associate with, indicating a multi-level system of regulation. This review will discuss the recent developments in how GPCRs are trafficked to the cell surface as newly synthesized receptors, their recruitment to the clathrin-mediated pathway for endocytosis, and their sorting to subsequent divergent post-endocytic fates, focusing primarily on hormone-activated GPCRs. Current models depicting the classic roles membrane trafficking plays in GPCR signaling have evolved to a highly regulated and complex system than previously appreciated. These developments impart key mechanistic information on how spatial and temporal aspects of GPCR signaling may be integrated and could provide pathway-specific targets to be exploited for therapeutic intervention.
Rivero-Müller A, Chou YY, Ji I, et al., 2010, Rescue of defective G protein-coupled receptor function in vivo by intermolecular cooperation, Proc Natl Acad Sci U S A, Vol: 2010 Jan 11. [Epub ahead of print]
G protein-coupled receptors (GPCRs) are ubiquitous mediators of signaling of hormones, neurotransmitters, and sensing. The old dogma is that a one ligand/one receptor complex constitutes the functional unit of GPCR signaling. However, there is mounting evidence that some GPCRs form dimers or oligomers during their biosynthesis, activation, inactivation, and/or internalization. This evidence has been obtained exclusively from cell culture experiments, and proof for the physiological significance of GPCR di/oligomerization in vivo is still missing. Using the mouse luteinizing hormone receptor (LHR) as a model GPCR, we demonstrate that transgenic mice coexpressing binding-deficient and signaling-deficient forms of LHR can reestablish normal LH actions through intermolecular functional complementation of the mutant receptors in the absence of functional wild-type receptors. These results provide compelling in vivo evidence for the physiological relevance of intermolecular cooperation in GPCR signaling.
Hanyaloglu AC, von Zastrow M, 2008, Regulation of GPCRs by Membrane Trafficking and Its Potential Implications, Annual Review of Pharmacology and Toxicology, Vol: Epub ahead of print
The endocytic pathway tightly controls the activity of G protein-coupled receptors (GPCRs). Ligand-induced endocytosis can drive receptors into divergent lysosomal and recycling pathways, producing essentially opposite effects on the strength and duration of cellular signaling via heterotrimeric G proteins, and may also promote distinct signaling events from intracellular membranes. This chapter reviews recent developments toward understanding the molecular machinery and functional implications of GPCR sorting in the endocytic pathway, focusing on mammalian GPCRs whose ligandinduced endocytosis is mediated primarily by clathrin-coated pits. Lysosomal sorting of a number of GPCRs occurs via a highly conserved mechanism requiring covalent tagging of receptors with ubiquitin. There is increasing evidence that additional, noncovalent mechanisms control the sorting of endocytosed GPCRs to lysosomes in mammalian cells. Recycling of several GPCRs to the plasma membrane is also specifically sorted, via a mechanism requiring both receptor-specific and shared sorting proteins. The current data reveal an unprecedented degree of specificity and plasticity in the cellular regulation of mammalian GPCRs by endocytic membrane trafficking. These developments have fundamental implications for GPCR pharmacology, and suggest new mechanisms that could be exploited in GPCR-directed pharmacotherapy.
Hanyaloglu AC, N'diaye EN, Kajihara KK, et al., 2008, The Ubiquitin-like Protein PLIC-2 Is a Negative Regulator of G Protein-coupled Receptor Endocytosis, Mol Biol Cell
The activity of many signaling receptors is regulated by their endocytosis via clathrin-coated pits (CCPs). For G protein-coupled receptors (GPCRs), recruitment of the adaptor protein arrestin to activated receptors is thought to be sufficient to drive GPCR clustering in CCPs and subsequent endocytosis. We have identified an unprecedented role for the ubiquitin-like protein PLIC-2 as a negative regulator of GPCR endocytosis. PLIC-2 overexpression delayed ligand-induced endocytosis of two GPCRs: the V2 vasopressin receptor and beta-2 adrenergic receptor, without affecting endocytosis of the Transferrin or EGF receptor. The closely related isoform PLIC-1 did not affect receptor endocytosis. PLIC-2 specifically inhibited GPCR concentration in CCPs, without affecting membrane recruitment of arrestin-3 to activated receptors or its cellular levels. Depletion of cellular PLIC-2 accelerated GPCR endocytosis, confirming its regulatory function at endogenous levels. The ubiquitin-like domain of PLIC-2, a ligand for ubiquitin-interacting motifs (UIM), was required for endocytic inhibition. Interestingly, the UIM-containing endocytic adaptors Eps15 and Epsin exhibited preferential binding to PLIC-2 over PLIC-1. This differential interaction may underlie PLIC-2 specific effect on GPCR endocytosis. Identification of a negative regulator of GPCR clustering reveals a new function of ubiquitin-like proteins and highlights a cellular requirement for exquisite regulation of receptor dynamics.
Hanyaloglu AC, von Zastrow M, 2007, A novel sorting sequence in the beta(2)-adrenergic receptor switches recycling from default to the Hrs-dependent mechanism, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 282, Pages: 3095-3104
Hanyaloglu A, Eidne K, 2007, Thyrotropin-releasing hormone receptors, xPharm: The Comprehensive Pharmacology Reference, Pages: 1-2, ISBN: 9780080552323
The tripeptide, thyrotropin-releasing hormone (L-pyroglutamyl-L-histidyl-L-prolinamide) acts on its receptors in the thyrotrope and lactotrope cells to promote secretion of TSH and prolactin, respectively. Aside from its well-known endocrine role in the thyroid system, TRH receptors are also thought to act as modulatory neuropeptides in the central nervous system. The cloning of a second receptor for TRH from rat brain and spinal cord provided a possible explanation for certain neurotransmitter actions of TRH, in particular the nociceptive and spinal cord regenerative actions. The two TRH receptor subtypes, TRH1 and TRH2, are found in several species, however, to date, the TRH2 receptor has not yet been identified in humans. © 2007 Elsevier Inc.
Hanyaloglu A, Eidne K, 2007, TRH-1 thyrotropin-releasing hormone receptor, xPharm: The Comprehensive Pharmacology Reference, Pages: 1-8, ISBN: 9780080552323
The tripeptide, thyrotropin-releasing hormone (L-pyroglutamyl-L-histidyl-L-prolinamide) acts on its receptors in the thyrotrope and lactotrope cells to promote secretion of TSH and prolactin, respectively. Aside from its well-known endocrine role in the thyroid system, TRH receptors are also thought to act as modulatory neuropeptides in the central nervous system. © 2007 Elsevier Inc.
Hanyaloglu A, Eidne K, 2007, TRH-2 thyrotropin-releasing hormone receptor, xPharm: The Comprehensive Pharmacology Reference, Pages: 1-6, ISBN: 9780080552323
The cloning of a second receptor for TRH from rat brain and spinal cord provided a possible explanation for certain neurotransmitter actions of TRH, in particular, the nociceptive and spinal cord regenerative actions. The two TRH receptor subtypes, TRH1 and TRH2, are found in several species, however, to date, the TRH2 receptor has not yet been identified in humans. © 2007 Elsevier Inc.
Hanyaloglu AC, McCullagh E, von Zastrow M, 2005, Essential role of Hrs in a recycling mechanism mediating functional resensitization of cell signaling, EMBO JOURNAL, Vol: 24, Pages: 2265-2283, ISSN: 0261-4189
Hanyaloglu AC, McCullagh E, von Zastrow M, 2004, Essential role of Hrs in a specialized recycling pathway mediating functional resensitization of cell signaling, Annual Meeting of the American-Society-for-Cell-Biology, Publisher: AMER SOC CELL BIOLOGY, Pages: 437A-437A, ISSN: 1059-1524
Ward BK, Magno AL, Davis EA, et al., 2004, Functional deletion of the calcium-sensing receptor in a case of neonatal severe hyperparathyroidism, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 89, Pages: 3721-3730, ISSN: 0021-972X
von Zastrow K, Deacon H, Gage R, et al., 2004, Regulation of G protein-coupled receptors by endocytosis, Annual Meeting of the Deutschen-Gesellschaft-fur-Zellbiologie, Publisher: URBAN & FISCHER VERLAG, Pages: 37-37, ISSN: 0171-9335
Miles LEC, Hanyaloglu AC, Dromey JR, et al., 2004, Gonadotropin-releasing hormone receptor-mediated growth suppression of immortalized L beta T2 gonadotrope and stable HEK293 cell lines, ENDOCRINOLOGY, Vol: 145, Pages: 194-204, ISSN: 0013-7227
Hanyaloglu AC, Seeber RM, Kohout TA, et al., 2002, Homo- and hetero-oligomerization of thyrotropin-releasing hormone (TRH) receptor subtypes - Differential regulation of beta-arrestins 1 and 2, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 277, Pages: 50422-50430, ISSN: 0021-9258
Eidne KA, Kroeger KM, Hanyaloglu AC, 2002, Applications of novel resonance energy transfer techniques to study dynamic hormone receptor interactions in living cells, TRENDS IN ENDOCRINOLOGY AND METABOLISM, Vol: 13, Pages: 415-421, ISSN: 1043-2760
Hanyaloglu AC, Kroeger KM, Eidne KA, 2002, G-protein coupled receptor oligomerization, Pharmaceutical News, Vol: 9, Pages: 317-325, ISSN: 1071-894X
Protein-protein interactions are fundamental processes for many biological systems including those involving the superfamily of G-protein coupled receptors (GPCRs). In particular, a growing body of biochemical and functional evidence has demonstrated the existence of GPCR-GPCR homo and heterooligomers. In particular, GPCR hetero-oligomers can display pharmacological and functional properties distinct from those of the homodimer or oligomer thus adding another level of complexity to how GPCRs are activated, signal and traffick in the cell. However, we are only beginning to unravel how and why such complexes are formed, the functional implications of which will have an enormous impact on GPCR biology. Future research that studies GPCRs as dimeric or oligomeric complexes will enhance not only our understanding of the GPCRs and cellular function, but will also be critical for novel drug design and improved treatment of the vast array of GPCR-related conditions.
Hanyaloglu AC, Vrecl M, Kroeger KM, et al., 2001, Casein kinase II sites in the intracellular C-terminal domain of the thyrotropin-releasing hormone receptor and chimeric gonadotropin-releasing hormone receptors contribute to beta-arrestin-dependent internalization, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 276, Pages: 18066-18074, ISSN: 0021-9258
Kroeger KM, Hanyaloglu AC, Eidne KA, 2001, Applications of BRET to study dynamic G-protein coupled receptor interactions in living cells, Pages: 155-162, ISSN: 0929-5666
Protein-protein interactions are fundamental processes for many biological systems including those involving the superfamily of G-protein coupled receptors (GPCRs). When addressing key questions concerning the regulation of GPCR-protein complexes and their functional significance, the development and refinement of non-invasive techniques to study these interactions will be of great value. One such technique, bioluminescence resonance energy transfer (BRET), is a recently described biophysical method that represents a powerful tool with which to measure protein-protein interactions in live cells, in real time. This minireview highlights the impact that evolving techniques such as BRET have had on the study of dynamic protein interactions involving GPCRs. In particular, the application of BRET to the study of protein interactions involving the receptors for hypothalamic peptide hormones, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH), will be discussed. Using these receptors, BRET has successfully been used to demonstrate formation of both agonist-dependent and independent GPCR-GPCR complexes (oligomerization) and the agonist-dependent interaction of GPCRs with their intracellular adaptor protein partners, the arrestins. In summary, BRET is a highly sensitive method that will not only aid in advancing our understanding of GPCR signalling and trafficking but could also potentially lead to the development of novel therapeutics that target these GPCR-protein complexes.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.