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1
Mangal, Suruchi, Manisha Sharma, Mridu Manjari, Rahul Mannan, and Sunit Tandon. "Expression Of Androgen Receptor, Estrogen Receptor And Progesterone Receptor In Endometrial Carcinoma (Immunohistochemical Study)." Annals of Pathology and Laboratory Medicine 7, no. 5 (May 28, 2020): A248–252. http://dx.doi.org/10.21276/apalm.2726.
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Johnstone, Elizabeth K. M., and Kevin D. G. Pfleger. "Profiling novel pharmacology of receptor complexes using Receptor-HIT." Biochemical Society Transactions 49, no. 4 (August 26, 2021): 1555–65. http://dx.doi.org/10.1042/bst20201110.
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Many receptors are able to undergo heteromerisation, leading to the formation of receptor complexes that may have pharmacological profiles distinct from those of the individual receptors. As a consequence of this, receptor heteromers can be classed as new drug targets, with the potential for achieving greater specificity and selectivity over targeting their constituent receptors. We have developed the Receptor-Heteromer Investigation Technology (Receptor-HIT), which enables the detection of receptor heteromers using a proximity-based reporter system such as bioluminescence resonance energy transfer (BRET). Receptor-HIT detects heteromers in live cells and in real time, by utilising ligand-induced signals that arise from altered interactions with specific biomolecules, such as ligands or proteins. Furthermore, monitoring the interaction between the receptors and the specific biomolecules generates functional information about the heteromer that can be pharmacologically quantified. This review will discuss various applications of Receptor-HIT, including its use with different classes of receptors (e.g. G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and others), its use to monitor receptor interactions both intracellularly and extracellularly, and also its use with genome-edited endogenous proteins.
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Nieber, Karen, and Sebastian Michael. "Adenosine receptors: Intermembrane receptor–receptor interactions in the brain." Synergy 1, no. 2 (December 2014): 83–91. http://dx.doi.org/10.1016/j.synres.2014.10.001.
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Ecke, Denise, Theodor Hanck, Mohan E. Tulapurkar, Rainer Schäfer, Matthias Kassack, Rolf Stricker, and Georg Reiser. "Hetero-oligomerization of the P2Y11 receptor with the P2Y1 receptor controls the internalization and ligand selectivity of the P2Y11 receptor." Biochemical Journal 409, no. 1 (December 11, 2007): 107–16. http://dx.doi.org/10.1042/bj20070671.
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Nucleotides signal through purinergic receptors such as the P2 receptors, which are subdivided into the ionotropic P2X receptors and the metabotropic P2Y receptors. The diversity of functions within the purinergic receptor family is required for the tissue-specificity of nucleotide signalling. In the present study, hetero-oligomerization between two metabotropic P2Y receptor subtypes is established. These receptors, P2Y1 and P2Y11, were found to associate together when co-expressed in HEK293 cells. This association was detected by co-pull-down, immunoprecipitation and FRET (fluorescence resonance energy transfer) experiments. We found a striking functional consequence of the interaction between the P2Y11 receptor and the P2Y1 receptor where this interaction promotes agonist-induced internalization of the P2Y11 receptor. This is remarkable because the P2Y11 receptor by itself is not able to undergo endocytosis. Co-internalization of these receptors was also seen in 1321N1 astrocytoma cells co-expressing both P2Y11 and P2Y1 receptors, upon stimulation with ATP or the P2Y1 receptor-specific agonist 2-MeS-ADP. 1321N1 astrocytoma cells do not express endogenous P2Y receptors. Moreover, in HEK293 cells, the P2Y11 receptor was found to functionally associate with endogenous P2Y1 receptors. Treatment of HEK293 cells with siRNA (small interfering RNA) directed against the P2Y1 receptor diminished the agonist-induced endocytosis of the heterologously expressed GFP–P2Y11 receptor. Pharmacological characteristics of the P2Y11 receptor expressed in HEK293 cells were determined by recording Ca2+ responses after nucleotide stimulation. This analysis revealed a ligand specificity which was different from the agonist profile established in cells expressing the P2Y11 receptor as the only metabotropic nucleotide receptor. Thus the hetero-oligomerization of the P2Y1 and P2Y11 receptors allows novel functions of the P2Y11 receptor in response to extracellular nucleotides.
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Doukhanina, Elena V., Nestor R. Apuya, Hye-Dong Yoo, Chuan-Yin Wu, Patricia Davidow, Shannon Krueger, Richard B. Flavell, Richard Hamilton, and Steven C. Bobzin. "Expression of Human Nuclear Receptors in Plants for the Discovery of Plant-Derived Ligands." Journal of Biomolecular Screening 12, no. 3 (January 26, 2007): 385–95. http://dx.doi.org/10.1177/1087057107299255.
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Plants have the potential to produce a wide array of secondary metabolites that have utility as drugs to treat human diseases. To tap this potential, functional human nuclear receptors have been expressed in plants to create in planta screening assays as a tool to discover natural product ligands. Assays have been designed and validated using 3 nuclear receptors: the estrogen receptor (ER), the androgen receptor (AR), and the heterodimeric retinoid X receptor-α plus thyroid hormone receptorβ (RXRA/THRB). Nuclear receptor—reporter constructs have been expressed in plants to detect the presence of natural ligands that are produced de novo in several plant species during different stages of development, in various tissues, and in response to different stress elicitors. Screening experiments with ER, AR, and RXRA/THRB have been conducted, leading to the identification of plant sources of natural product ligands of human nuclear receptors. This in planta screen has led to the identification of previously unreported ER ligands, providing evidence of the complementary value of this approach to current in vitro high-throughput screening assays. ( Journal of Biomolecular Screening 2007:385-395)
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Presky, D. H., U. Gubler, R. A. Chizzonite, and M. K. Gately. "IL12 receptors and receptor antagonists." Research in Immunology 146, no. 7-8 (September 1995): 439–45. http://dx.doi.org/10.1016/0923-2494(96)83013-6.
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Hu, Wenhui, Sunila Mahavadi, Jiean Huang, Fang Li, and Karnam S. Murthy. "Characterization of S1P1 and S1P2 receptor function in smooth muscle by receptor silencing and receptor protection." American Journal of Physiology-Gastrointestinal and Liver Physiology 291, no. 4 (October 2006): G605—G610. http://dx.doi.org/10.1152/ajpgi.00147.2006.
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Sphingosine-1-phosphate (S1P) induces an initial Ca2+-dependent contraction followed by a sustained Ca2+-independent, RhoA-mediated contraction in rabbit gastric smooth muscle cells. The cells coexpress S1P1 and S1P2 receptors, but the signaling pathways initiated by each receptor type and the involvement of one or both receptors in contraction are not known. Lentiviral vectors encoding small interfering RNAs were transiently transfected into cultured smooth muscle cells to silence S1P1 or S1P2 receptors. Phospholipase C (PLC)-β activity and Rho kinase activity were used as markers of pathways mediating initial and sustained contraction, respectively. Silencing of S1P1 receptors abolished S1P-stimulated activation of Gαi3 and partially inhibited activation of Gαi1, whereas silencing of S1P2 receptors abolished activation of Gαq, Gα13, and Gαi2 and partially inhibited activation of Gαi1. Silencing of S1P2 but not S1P1 receptors suppressed S1P-stimulated PLC-β and Rho kinase activities, implying that both signaling pathways were mediated by S1P2 receptors. The results obtained by receptor silencing were corroborated by receptor inactivation. The selective S1P1 receptor agonist SEW2871 did not stimulate PLC-β or Rho kinase activity or induce initial and sustained contraction; when this agonist was used to protect S1P1 receptors so as to enable chemical inactivation of S1P2 receptors, S1P did not elicit contraction, confirming that initial and sustained contraction was mediated by S1P2 receptors. Thus S1P1 and S1P2 receptors are coupled to distinct complements of G proteins. Only S1P2 receptors activate PLC-β and Rho kinase and mediate initial and sustained contraction.
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Mika, Kaan, Steeve Cruchet, Phing Chian Chai, Lucia L. Prieto-Godino, Thomas O. Auer, Sylvain Pradervand, and Richard Benton. "Olfactory receptor–dependent receptor repression in Drosophila." Science Advances 7, no. 32 (August 2021): eabe3745. http://dx.doi.org/10.1126/sciadv.abe3745.
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In olfactory systems across phyla, most sensory neurons express a single olfactory receptor gene selected from a large genomic repertoire. We describe previously unknown receptor gene–dependent mechanisms that ensure singular expression of receptors encoded by a tandem gene array [Ionotropic receptor 75c (Ir75c), Ir75b, and Ir75a, organized 5′ to 3′] in Drosophila melanogaster. Transcription from upstream genes in the cluster runs through the coding region of downstream loci and inhibits their expression in cis, most likely via transcriptional interference. Moreover, Ir75c blocks accumulation of other receptor proteins in trans through a protein-dependent, posttranscriptional mechanism. These repression mechanisms operate in endogenous neurons, in conjunction with cell type–specific gene regulatory networks, to ensure unique receptor expression. Our data provide evidence for inter-olfactory receptor regulation in invertebrates and highlight unprecedented, but potentially widespread, mechanisms for ensuring exclusive expression of chemosensory receptors, and other protein families, encoded by tandemly arranged genes.
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Arellano-Saab, Amir, Michael Bunsick, Hasan Al Galib, Wenda Zhao, Stefan Schuetz, James Michael Bradley, Zhenhua Xu, et al. "Three mutations repurpose a plant karrikin receptor to a strigolactone receptor." Proceedings of the National Academy of Sciences 118, no. 30 (July 23, 2021): e2103175118. http://dx.doi.org/10.1073/pnas.2103175118.
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Uncovering the basis of small-molecule hormone receptors’ evolution is paramount to a complete understanding of how protein structure drives function. In plants, hormone receptors for strigolactones are well suited to evolutionary inquiries because closely related homologs have different ligand preferences. More importantly, because of facile plant transgenic systems, receptors can be swapped and quickly assessed functionally in vivo. Here, we show that only three mutations are required to turn the nonstrigolactone receptor, KAI2, into a receptor that recognizes the plant hormone strigolactone. This modified receptor still retains its native function to perceive KAI2 ligands. Our directed evolution studies indicate that only a few keystone mutations are required to increase receptor promiscuity of KAI2, which may have implications for strigolactone receptor evolution in parasitic plants.
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De Weerth, A., J. R. Pisegna, and S. A. Wank. "Guinea pig gallbladder and pancreas possess identical CCK-A receptor subtypes: receptor cloning and expression." American Journal of Physiology-Gastrointestinal and Liver Physiology 265, no. 6 (December 1, 1993): G1116—G1121. http://dx.doi.org/10.1152/ajpgi.1993.265.6.g1116.
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Cholecystokinin (CCK) receptors mediate pancreatic acinar secretion and gallbladder contraction. Pharmacological and functional studies in pancreas and gallbladder demonstrate a CCK-A receptor subtype in both tissues. However, some pharmacological studies and affinity cross-linking studies of CCK receptors on pancreatic acini and gallbladder suggest that these two tissues possess two different subtypes of the CCK-A receptor. We cloned these receptors in guinea pig using a cDNA clone of the CCK-A receptor from rat pancreas. The guinea pig gallbladder CCK-A receptor was cloned by hybridization screening of a gallbladder cDNA library using a cDNA probe from the rat CCK-A receptor coding region. The guinea pig pancreas CCK-A receptor cDNA was cloned via the polymerase chain reaction using primers corresponding to the guinea pig gallbladder CCK-A receptor 5'- and 3'-noncoding regions. CCK-A receptor clones from guinea pig pancreas and gallbladder had identical nucleotide sequences, which were 80% homologous to the rat CCK-A receptor cDNA sequence. The deduced amino acid sequence from guinea pig CCK-A receptors was 89% homologous to the rat CCK-A receptor sequence. Dose-inhibition binding studies of transiently expressed receptors by CCK agonists and antagonists exhibited a CCK-A receptor pharmacologically similar to the rat CCK-A receptor. These studies indicate that the CCK-A receptors in guinea pig pancreas and gallbladder are identical and do not support previous proposals that they may represent different receptor subtypes.
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Agnati, Luigi F., Giuseppina Leo, Susanna Genedani, Diego Guidolin, Nicola Andreoli, and Kjell Fuxe. "Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease." Scientific World JOURNAL 7 (2007): 1073–81. http://dx.doi.org/10.1100/tsw.2007.166.
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It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers), but clusters of receptors (receptor mosaics), altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.
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Dlugosz, Paula, and Johannes Nimpf. "The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor." International Journal of Molecular Sciences 19, no. 10 (October 9, 2018): 3090. http://dx.doi.org/10.3390/ijms19103090.
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Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor belong to the low density lipoprotein receptor family and bind apolipoprotein E. These receptors interact with the clathrin machinery to mediate endocytosis of macromolecules but also interact with other adapter proteins to perform as signal transduction receptors. The best characterized signaling pathway in which ApoER2 and VLDL receptor (VLDLR) are involved is the Reelin pathway. This pathway plays a pivotal role in the development of laminated structures of the brain and in synaptic plasticity of the adult brain. Since Reelin and apolipoprotein E, are ligands of ApoER2 and VLDLR, these receptors are of interest with respect to Alzheimer’s disease. We will focus this review on the complex structure of ApoER2 and VLDLR and a recently characterized ligand, namely clusterin.
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Fuller, Peter J., and Morag J. Young. "Duelling Receptors: Estrogen Receptor Versus Mineralocorticoid Receptor in the Cardiovascular System." Endocrinology 155, no. 11 (November 1, 2014): 4117–19. http://dx.doi.org/10.1210/en.2014-1778.
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Crass, Torsten, Robert S. Ames, Henry M. Sarau, Mark A. Tornetta, James J. Foley, Jörg Köhl, Andreas Klos, and Wilfried Bautsch. "Chimeric Receptors of the Human C3a Receptor and C5a Receptor (CD88)." Journal of Biological Chemistry 274, no. 13 (March 26, 1999): 8367–70. http://dx.doi.org/10.1074/jbc.274.13.8367.
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Ohlstein, Eliot H., John D. Elliott, Giora Z. Feuerstein, and Robert R. Ruffolo. "Endothelin receptors: Receptor classification, novel receptor antagonists, and potential therapeutic targets." Medicinal Research Reviews 16, no. 4 (July 1996): 365–90. http://dx.doi.org/10.1002/(sici)1098-1128(199607)16:4<365::aid-med4>3.0.co;2-v.
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Mihajlović, Ljubiša, Milica Mihajlović, and Vladan Mihajlović. "Molekularni mehanizam patogenog delovanja virusa SARS-CoV-2, uloga ACE2 receptora u generisanju surfaktanta i održanju stabilnosti velikih funkcionalnih površina." Timocki medicinski glasnik 46, no. 4 (2021): 178–84. http://dx.doi.org/10.5937/tmg2104178m.
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Virus SARS-CoV-2 uzrokuje COVID-19 vezivanjem za ACE2 receptor. SARS-CoV-2 se za razliku od ostalih korona virusa intenzivnije vezuje za ACE2 receptor. Ekspresija ACE2 receptora je posebno karakteristična za ćelije alveolarnog tipa 2, endotelne ćelije malih i velikih arterija i ćelije glatkih mišića arterija, enterocite tankog creva, Leidigove i Sertolijeve ćelije, proksimalne ćelije bubrežnih tubula i ćelija creva. Zajednička karakteristika ćelija, tkiva i organa, koji imaju visoku ekspresiju ACE2, je da imaju "veliku funkcionalnu površinu". ACE2 receptor je kritičan za održavanje integriteta i stabilnosti "velikih funkcionalnih površina" u tim organima. Stabilnost "velikih funkcionalnih površina" ACE2 receptor realizuje produkcijom površinskih stabilizatora, surfaktanata. Uloga surfaktanata je stabilizacija i imunoprotekcija velikih funkcionalnih površina. Osobe sa manjom ekspresijom ACE2 receptora (gojazni, stariji, osobe sa komorbiditetima, muškarci) su podložnije COVID-19. Vezivanjem za ACE2 receptore, SARS-CoV-2 blokira produkciju surfaktanta u tolikoj meri da antigeni "velikih funkcionalnih površina" postaju "vidljivi" odbrambenom, imunoiloškom sistemu organizma. Tako nastaju upalne i druge simptomatske reakcije karakteristične za COVID-19. Odatle sledi, da je molekularni mehanizam patološkog dejstva virusa SARS-CoV-2 u slučaju COVID-19 najverovatnije uzrokovan inhibicijom ACE2 receptora i smanjenom produkcijom surfaktanta. Ostaju dalje provere u tom pravcu.
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Agnati, Luigi F., Diego Guidolin, Chiara Cervetto, Dasiel O. Borroto-Escuela, and Kjell Fuxe. "Role of iso-receptors in receptor-receptor interactions with a focus on dopamine iso-receptor complexes." Reviews in the Neurosciences 27, no. 1 (January 1, 2016): 1–25. http://dx.doi.org/10.1515/revneuro-2015-0024.
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AbstractIntercellular and intracellular communication processes consist of signals and recognition/decoding apparatuses of these signals. In humans, the G protein-coupled receptor (GPCR) family represents the largest family of cell surface receptors. More than 30 years ago, it has been proposed that GPCR could form dimers or higher-order oligomers (receptor mosaics [RMs] at the plasma membrane level and receptor-receptor interactions [RRIs] have been proposed as a new integrative mechanism for chemical signals impinging on cell plasma membranes). The basic phenomena involved in RRIs are allostery and cooperativity of membrane receptors, and the present paper provides basic information concerning their relevance for the integrative functions of RMs. In this context, the possible role of iso-receptor RM is discussed (with a special focus on dopamine receptor subtypes and on some of the RMs they form with other dopamine iso-receptors), and it is proposed that two types of cooperativity, namely, homotropic and heterotropic cooperativity, could allow distinguishing two types of functionally different RMs. From a general point of view, the presence of iso-receptors and their topological organization within RMs allow the use of a reduced number of signals for the intercellular communication processes, since the target cells can recognize and decode the same signal in different ways. This theoretical aspect is further analyzed here by means of an analogy with artificial information systems. Thus, it is suggested that the ‘multiplexer’ and ‘demultiplexer’ concepts could, at least in part, model the role of RMs formed by iso-receptors in the information handling by the cell.
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Smith, D. M., H. A. Coppock, D. J. Withers, A. A. Owji, D. L. Hay, T. P. Choksi, P. Chakravarty, S. Legon, and D. R. Poyne. "Adrenomedullin: receptor and signal transduction." Biochemical Society Transactions 30, no. 4 (August 1, 2002): 432–37. http://dx.doi.org/10.1042/bst0300432.
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Adrenomedullin is a vascular tissue peptide and a member of the calcitonin family of peptides, which includes calcitonin, calcitonin-gene-related peptide (CGRP) and amylin. Its many biological actions are mediated via CGRP type 1 (CGRP1) receptors and by specific adrenomedullin receptors. Although the pharmacology of these receptors is distinct, they are both represented in molecular terms by the type II family G-protein-coupled receptor, calcitonin-receptor-like receptor (CRLR). The specificity here is defined by co-expression of receptor-activity-modifying proteins (RAMPs). CGRP1 receptors are represented by CRLR and RAMP1, and specific adrenomedullin receptors by CRLR and RAMP2 or 3. Here we discuss how CRLR/RAMP2 relates to adrenomedullin binding, pharmacology and pathophysiology, and how chemical cross-linking of receptor-ligand complexes in tissue relates to that in CRLR/RAMP2-expressing cells. CRLR, like other type II family G-protein-coupled receptors, signals via Gs and adenylate cyclase activation. We demonstrated that adrenomedullin signalling in cell lines expressing specific adrenomedullin receptors followed this expected pattern.
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Villela, Daniel, Julia Leonhardt, Neal Patel, Jason Joseph, Sebastian Kirsch, Anders Hallberg, Thomas Unger, et al. "Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison." Clinical Science 128, no. 4 (October 17, 2014): 227–34. http://dx.doi.org/10.1042/cs20130515.
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The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin–angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking similarities. Moreover, in some instances, antagonists for one receptor are able to inhibit the action of agonists for the respective other receptor. These observations suggest that there may be a functional or even physical interaction of both receptors. This article discusses potential mechanisms underlying the phenomenon of blockade of angiotensin-(1–7) [Ang-(1–7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1–7) metabolite alamandine and its receptor MrgD in the observed effects. We conclude that evidence for a functional interaction of both receptors is strong, but that such an interaction may be species- and/or tissue-specific and that elucidation of the precise nature of the interaction is only at the very beginning.
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Dunn, W. A., T. P. Connolly, and A. L. Hubbard. "Receptor-mediated endocytosis of epidermal growth factor by rat hepatocytes: receptor pathway." Journal of Cell Biology 102, no. 1 (January 1, 1986): 24–36. http://dx.doi.org/10.1083/jcb.102.1.24.
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Substantial amounts of epidermal growth factor (EGF) are cleared from the circulation by hepatocytes via receptor-mediated endocytosis and subsequently degraded within lysosomes. We have used a combined biochemical and morphological approach to examine the fate of the receptor after exposure to EGF. Polyclonal antibodies were prepared against the purified receptor and their specificity established by immunoprecipitation and immunoblotting techniques. The EGF receptor was then localized by immunofluorescence and immunoperoxidase techniques and quantified on immunoblots. In untreated livers, EGF receptor was restricted to the sinusoidal and lateral surfaces of hepatocytes. 2-4 min after exposure of cells to EGF, the receptor was found in small vesicles (i.e., coated vesicles) as well as larger vesicles and tubules at the cell periphery. By 15 min the receptor was found in multivesicular endosomes located near bile canaliculi. Exposure of hepatocytes to EGF also resulted in a rapid loss of receptor protein from total liver homogenates and a decrease in its half-life from 8.7 h in control livers to 2.5 h. This EGF-induced loss of receptors was not observed when lysosomal proteinases were inhibited by leupeptin or when endosome/lysosome fusion was prevented by low temperature (16 degrees C). In the presence of leupeptin, receptor could be detected in structures identified as lysosomes using acid-phosphatase cytochemistry. All these results suggested rapid internalization of EGF receptors in response to ligand and degradation within lysosomes. However, four times more ligand was degraded at 8 h than the number of high-affinity (Kd of 8-15 nM) EGF-binding sites lost, suggesting either (a) high-affinity receptors were recycled, and/or (b) more than 300,000 receptors were available for EGF uptake. We identified and characterized a latent pool of approximately 300,000 low-affinity receptors (Kd approximately 200 nM) that could be separated on sucrose gradients from the plasma membrane pool of approximately 300,000 high-affinity receptors (Kd of 8-15 nM). Despite the differences in their binding affinities, the high- and low-affinity receptors appeared to be structurally identical and were both EGF-dependent protein kinases. In addition, the dynamics of the low-affinity receptors were consistent with a functional role in EGF uptake and delivery to lysosomes.
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Divekar, Shailaja D., Deanna M. Tiek, Aileen Fernandez, and Rebecca B. Riggins. "Estrogen-related Receptor β (ERRβ) – Renaissance Receptor or Receptor Renaissance?" Nuclear Receptor Signaling 14, no. 1 (January 2016): nrs.14002. http://dx.doi.org/10.1621/nrs.14002.
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Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα (ESRRA) and ERRγ (ESRRG) at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ (ESRRB), however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor.
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Gurnell, Mark, and V. Krishna K. Chatterjee. "Nuclear receptors in disease: thyroid receptor beta, peroxisome-proliferator-activated receptor gamma and orphan receptors." Essays in Biochemistry 40 (June 1, 2004): 169–89. http://dx.doi.org/10.1042/bse0400169.
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The nuclear receptor superfamily comprises a group of proteins that includes the molecular targets for classical steroid hormones such as glucocorticoids, androgens and vitamin D, together with a number of so-called 'orphan' receptors whose ligands and/or function remain to be determined. Many of the world's most commonly prescribed drugs act via nuclear receptors, attesting to their importance as therapeutic targets in human disease [for example, the novel anti-diabetic thiazolidinediones rosiglitazone and pioglitazone are high-affinity ligands for peroxisome-proliferator-activated receptor gamma (PPARgamma)]. The study of transgenic mice harbouring global and tissue-specific alterations in nuclear receptor genes has greatly enhanced our understanding of the roles that these receptors play in mammalian physiology. In many cases, these findings have been complemented by the study of human subjects harbouring naturally occurring mutations within the corresponding receptor, whereas in others, such studies have served to highlight important differences that exist between human and mouse physiology especially, for example, in relation to aspects of metabolism. Here we review the diverse clinical phenotypes that have been reported in subjects found to have germline mutations in thyroid hormone receptor beta, PPARgamma, hepatocyte nuclear factor 4alpha, small heterodimer partner, steroidogenic factor 1, DAX1, photoreceptor-specific nuclear receptor and NUR-related factor 1, and consider the molecular mechanisms through which aberrant signalling by mutant receptors might contribute to the pathogenesis of the associated disorders.
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Sitaraman, Shanthi V., Mustapha Si-Tahar, Didier Merlin, Gregg R. Strohmeier, and J. L. Madara. "Polarity of A2b adenosine receptor expression determines characteristics of receptor desensitization." American Journal of Physiology-Cell Physiology 278, no. 6 (June 1, 2000): C1230—C1236. http://dx.doi.org/10.1152/ajpcell.2000.278.6.c1230.
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It is not known if, in polarized cells, desensitization events can be influenced by the domain on which the receptor resides. Desensitization was induced by 5′-( N-ethylcarboxamido)adenosine (NECA) and was quantitated by measurement of short-circuit current ( I sc) in response to adenosine. NECA added to either the apical or basolateral compartments rapidly desensitized receptors on these respective domains. Although apical NECA had no effect on the basolateral receptor stimulation, basolateral NECA induced a complete desensitization of the apical receptor. We hypothesized that desensitization of apical receptor by basolateral desensitization could relate to a trafficking step in which A2b receptor is first targeted basolaterally upon synthesis and transported to the apical surface via vesicular transport/microtubules. Because desensitization is associated with downregulation of receptors, apical adenosine receptor can thus be affected by basolateral desensitization. Both low temperature and nocodazole inhibited I scinduced by apical and not basolateral adenosine. In conclusion: 1) a single receptor subtype, here modeled by the A2b receptor, differentially desensitizes based on the membrane domain on which it is expressed, 2) agonist exposure on one domain can result in desensitization of receptors on the opposite domain, 3) cross-domain desensitization can display strict polarity, and 4) receptor trafficking may play a role in the cross-desensitization process.
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Weigel, Nancy L., and Nicole L. Moore. "Steroid Receptor Phosphorylation: A Key Modulator of Multiple Receptor Functions." Molecular Endocrinology 21, no. 10 (October 1, 2007): 2311–19. http://dx.doi.org/10.1210/me.2007-0101.
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Abstract Steroid receptors are hormone-activated transcription factors, the expression and activities of which are also highly dependent upon posttranslational modifications including phosphorylation. The remarkable number of phosphorylation sites in these receptors and the wide variety of kinases participating in their phosphorylation facilitate integration between cell-signaling pathways and steroid receptor action. Sites have been identified in all of the functional domains although the sites are predominantly in the amino-terminal portions of the receptors. Regulation of function is receptor specific, site specific, and often dependent upon activation of a specific cell-signaling pathway. This complexity explains, in part, the early difficulties in identifying roles for phosphorylation in receptor function. With increased availability of phosphorylation site-specific antibodies and better means to measure receptor activities, numerous roles for site-specific phosphorylation have been identified including sensitivity of response to hormone, DNA binding, expression, stability, subcellular localization, and protein-protein interactions that determine the level of regulation of specific target genes. This review summarizes current knowledge regarding receptor phosphorylation and regulation of function. As functional assays become more sophisticated, it is likely that additional roles for phosphorylation in receptor function will be identified.
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Zampieri, N., and M. V. Chao. "Mechanisms of neurotrophin receptor signalling." Biochemical Society Transactions 34, no. 4 (July 21, 2006): 607–11. http://dx.doi.org/10.1042/bst0340607.
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Regulation of cell survival decisions and neuronal plasticity by neurotrophins are mediated by two classes of receptors, Trks (tropomyosin receptor kinases) and p75, the first discovered member of the tumour necrosis factor receptor superfamily. The p75 receptor participates with the TrkA receptor in the formation of high-affinity nerve growth factor-binding sites to promote survival under limiting concentrations of neurotrophins. Activation of Trk receptors leads to increased phosphorylation of Shc (Src homology and collagen homology), phospholipase C-γ and novel adaptor molecules, such as the ARMS (ankyrin-rich membrane spanning)/Kidins220 protein. Small ligands that interact with G-protein-coupled receptors can also activate Trk receptor kinase activity. Transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecules to elicit neuroprotective effects for the treatment of neurodegenerative diseases. Like amyloid precursor protein and Notch, p75 is a substrate for γ-secretase cleavage. The p75 receptor undergoes an α-secretase-mediated release of the extracellular domain followed by a γ-secretase-mediated intramembrane cleavage. Cleavage of p75 may represent a general mechanism for transmitting signals as an independent receptor and as a co-receptor for other signalling systems.
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Modrall, J. Gregory, Masakatsu Nanamori, Junichi Sadoshima, Douglas C. Barnhart, James C. Stanley, and Richard R. Neubig. "ANG II type 1 receptor downregulation does not require receptor endocytosis or G protein coupling." American Journal of Physiology-Cell Physiology 281, no. 3 (September 1, 2001): C801—C809. http://dx.doi.org/10.1152/ajpcell.2001.281.3.c801.
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ANG II type 1 (AT1) receptors respond to sustained exposure to ANG II by undergoing downregulation of absolute receptor numbers. It has been assumed previously that downregulation involves endocytosis. The present study hypothesized that AT1 receptor downregulation occurs independently of receptor endocytosis or G protein coupling. Mutant AT1 receptors with carboxy-terminal deletions internalized <5% of radioligand compared with 65% for wild-type AT1 receptors. The truncated AT1 receptors retained the ability to undergo downregulation. These data suggest the existence of an alternative pathway to AT1 receptor degradation that does not require endocytosis, per se. Point mutations in either the second transmembrane region or second intracellular loop impaired G protein (Gq) coupling. These receptors exhibited a biphasic pattern of downregulation. The earliest phase of downregulation (0–2 h) was independent of coupling to Gq, but no additional downregulation was observed after 2 h of ANG II exposure in the receptors with impaired coupling to Gq. These data suggest that coupling to Gq is required for the later phase (2–24 h) of AT1 receptor downregulation.
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Mineo, Chieko. "Lipoprotein receptor signalling in atherosclerosis." Cardiovascular Research 116, no. 7 (December 13, 2019): 1254–74. http://dx.doi.org/10.1093/cvr/cvz338.
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Abstract The founding member of the lipoprotein receptor family, low-density lipoprotein receptor (LDLR) plays a major role in the atherogenesis through the receptor-mediated endocytosis of LDL particles and regulation of cholesterol homeostasis. Since the discovery of the LDLR, many other structurally and functionally related receptors have been identified, which include low-density lipoprotein receptor-related protein (LRP)1, LRP5, LRP6, very low-density lipoprotein receptor, and apolipoprotein E receptor 2. The scavenger receptor family members, on the other hand, constitute a family of pattern recognition proteins that are structurally diverse and recognize a wide array of ligands, including oxidized LDL. Among these are cluster of differentiation 36, scavenger receptor class B type I and lectin-like oxidized low-density lipoprotein receptor-1. In addition to the initially assigned role as a mediator of the uptake of macromolecules into the cell, a large number of studies in cultured cells and in in vivo animal models have revealed that these lipoprotein receptors participate in signal transduction to modulate cellular functions. This review highlights the signalling pathways by which these receptors influence the process of atherosclerosis development, focusing on their roles in the vascular cells, such as macrophages, endothelial cells, smooth muscle cells, and platelets. Human genetics of the receptors is also discussed to further provide the relevance to cardiovascular disease risks in humans. Further knowledge of the vascular biology of the lipoprotein receptors and their ligands will potentially enhance our ability to harness the mechanism to develop novel prophylactic and therapeutic strategies against cardiovascular diseases.
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Aymerich, María S., J. López-Azcárate, J. Bonaventura, G. Navarro, D. Fernández-Suárez, V. Casadó, F. Mayor, et al. "Real-Time G-Protein-Coupled Receptor Imaging to Understand and Quantify Receptor Dynamics." Scientific World JOURNAL 11 (2011): 1995–2010. http://dx.doi.org/10.1100/2011/690858.
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Understanding the trafficking of G-protein-coupled receptors (GPCRs) and their regulation by agonists and antagonists is fundamental to develop more effective drugs. Optical methods using fluorescent-tagged receptors and spinning disk confocal microscopy are useful tools to investigate membrane receptor dynamics in living cells. The aim of this study was to develop a method to characterize receptor dynamics using this system which offers the advantage of very fast image acquisition with minimal cell perturbation. However, in short-term assays photobleaching was still a problem. Thus, we developed a procedure to perform a photobleaching-corrected image analysis. A study of short-term dynamics of the long isoform of the dopamine type 2 receptor revealed an agonist-induced increase in the mobile fraction of receptors with a rate of movement of 0.08 μm/s For long-term assays, the ratio between the relative fluorescence intensity at the cell surface versus that in the intracellular compartment indicated that receptor internalization only occurred in cells co-expressing G protein-coupled receptor kinase 2. These results indicate that the lateral movement of receptors and receptor internalization are not directly coupled. Thus, we believe that live imaging of GPCRs using spinning disk confocal image analysis constitutes a powerful tool to study of receptor dynamics.
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Hollenberg, M. D., M. Saifeddine, B. Al-Ani, and A. Kawabata. "Proteinase-activated receptors: structural requirements for activity, receptor cross-reactivity, and receptor selectivity of receptor-activating peptides." Canadian Journal of Physiology and Pharmacology 75, no. 7 (July 1, 1997): 832–41. http://dx.doi.org/10.1139/y97-110.
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Ismael, Amber, Wei Tian, Nicholas Waszczak, Xin Wang, Youfang Cao, Dmitry Suchkov, Eli Bar, et al. "Gβ promotes pheromone receptor polarization and yeast chemotropism by inhibiting receptor phosphorylation." Science Signaling 9, no. 423 (April 12, 2016): ra38. http://dx.doi.org/10.1126/scisignal.aad4376.
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Gradient-directed cell migration (chemotaxis) and growth (chemotropism) are processes that are essential to the development and life cycles of all species. Cells use surface receptors to sense the shallow chemical gradients that elicit chemotaxis and chemotropism. Slight asymmetries in receptor activation are amplified by downstream signaling systems, which ultimately induce dynamic reorganization of the cytoskeleton. During the mating response of budding yeast, a model chemotropic system, the pheromone receptors on the plasma membrane polarize to the side of the cell closest to the stimulus. Although receptor polarization occurs before and independently of actin cable–dependent delivery of vesicles to the plasma membrane (directed secretion), it requires receptor internalization. Phosphorylation of pheromone receptors by yeast casein kinase 1 or 2 (Yck1/2) stimulates their internalization. We showed that the pheromone-responsive Gβγ dimer promotes the polarization of the pheromone receptor by interacting with Yck1/2 and locally inhibiting receptor phosphorylation. We also found that receptor phosphorylation is essential for chemotropism, independently of its role in inducing receptor internalization. A mathematical model supports the idea that the interaction between Gβγ and Yck1/2 results in differential phosphorylation and internalization of the pheromone receptor and accounts for its polarization before the initiation of directed secretion.
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Presti, M. E., and J. D. Gardner. "Receptor antagonists for gastrointestinal peptides." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 3 (March 1, 1993): G399—G406. http://dx.doi.org/10.1152/ajpgi.1993.264.3.g399.
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Receptors for gastrointestinal peptides are all G protein-coupled receptors. Since the discovery that dibutyryl guanosine 3',5'-cyclic monophosphate was a cholecystokinin-receptor antagonist, a variety of receptor antagonists have been developed for a number of different gastrointestinal peptides. These antagonists have been useful in classifying receptors for gastrointestinal peptides and in elucidating complex regulation of gastrointestinal function. Some antagonists also have therapeutic potential. Based on the receptors with which they interact, gastrointestinal peptides can be grouped into families, and, in general, a given receptor antagonist is specific for a given family. This review covers the different families of gastrointestinal peptides and the major antagonists that exist for each family.
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McCarthy, James R., Stephen C. Heinrichs, and Dimitri E. Grigoriadis. "Recent Advances with the CRF1 Receptor: Design of Small Molecule Inhibitors, Receptor Subtypes and Clinical Indications." Current Pharmaceutical Design 5, no. 5 (May 1999): 289–315. http://dx.doi.org/10.2174/138161280505230110095255.
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Abstract: Corticotropin-releasing factor (CRF) has been widely implicated as playing a major role in modulating the endocrine, autonomic, behavioral and immune responses to stress. The recent cloning of multiple receptors for CRF as well as the discovery of non-peptide receptor antagonists for CRF receptors have begun a new era of CRF study. Presently, there are five distinct targets for CRF with unique cDNA sequences, pharmacology and localization. These fall into three distinct classes, encoded by three different genes and have been termed the CRF1 and CRF2 receptors (belonging to the superfamily of G-protein coupled receptors) and the CRF-binding protein. The CRF2 receptor exists as three splice variants of the same gene and have been designated CRF2α CRF2β and CRF2γ- The pharmacology and localization of all of these proteins in brain has been well established. The CRF I receptor subtype is localized primarily to cortical and cerebellar regions ·while the CRF2α receptor is localized to subcortical regions including the lateral septum, and paraventricular and ventromedial nuclei of the hypothalamus. The CRF2β receptor is primarily localized to heart, skeletal muscle and in the brain, to cerebral arterioles and choroid plexus. TheCRF2γ receptor has most recen\ly been identified in human amygdala. Expression of these receptors in mammalian cell lines has made possible the identification of non-peptide, high affinity, selective receptor antagonists. While the natural mammalian ligands oCRF and r/hCRF have high affinity for the CRF I receptor subtype, they have lower affiruty for the CRF2 receptor family making them ineffective labels for CRF2 receptors. [125I]Sauvagine has been characterized as a high affinity ligand for both the CRF1 and the CRF2 receptor subtypes and has been used in both radioligand bindii:ig and receptor autoradiographic studies as a tool to aid in the discovery of selective small molecule receptor antagonists. A number of non-peptide CRF1 receptor antagonists that can specifically and selectively block the CRF1 receptor subtype have recently been identified. Compounds such as CP 154,526 (12), NB! 279 l 4 (129) and Antalarmin (154) inhibit CRF-stimulation of cAMP or CRF-stimulated ACTH release from cultured rat anterior pituitary cells. Furthermore, when administered peripherally, these compounds compete for ex vivo [125l]sauvagine binding to CRF I receptors in brain sections demonstrating their ability to cross the blood-brain-barrier. ln in vivo studies, peripheral administration of these compounds attenuate stress-induced elevations in plasma ACTH levels in rats demonstrating that CRF1 receptors can be blocked in the periphery. Furthermore, peripherally administered CRF1 receptor antagonists have also been demonstrated to inhibit CRF-induced seizure activity. These data clearly demonstrate \hat non-peptide CRF1 receptor antagonists, when administered systemically, can specifically block central CRF1 receptors and provide tools that can be used to determine the role of CRF1 receptors in various neuropsychiatric and neurodegenerative disorders. In addition, these molecules will prove useful in the discovery and development of potential orally active therapeutics for these disorders.
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Matsuoka, Toshiyuki, and Shuh Narumiya. "Prostaglandin Receptor Signaling in Disease." Scientific World JOURNAL 7 (2007): 1329–47. http://dx.doi.org/10.1100/tsw.2007.182.
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Prostanoids, consisting of the prostaglandins (PGs) and the thromboxanes (TXs), are a group of lipid mediators formed in response to various stimuli. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. They are released outside of the cells immediately after synthesis, and exert their actions by binding to a G-protein coupled rhodopsin-type receptor on the surface of target cells. There are eight types of the prostanoid receptors conserved in mammals from mouse to human. They are the PGD receptor (DP), four subtypes of the PGE receptor (EP1, EP2, EP3, and EP4), the PGF receptor (FP), PGI receptor (IP), and TXA receptor (TP). Recently, mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease. These studies have revealed the roles of PG receptor signaling in various pathological conditions, and suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of the pathological conditions. Here we review these recent findings of roles of prostanoid receptor signaling and their therapeutic implications.
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Philipp, Melanie, Marc Brede, and Lutz Hein. "Physiological significance of α2-adrenergic receptor subtype diversity: one receptor is not enough." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 283, no. 2 (August 1, 2002): R287—R295. http://dx.doi.org/10.1152/ajpregu.00123.2002.
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α2-Adrenergic receptors mediate part of the diverse biological effects of the endogenous catecholamines epinephrine and norepinephrine. Three distinct subtypes of α2-adrenergic receptors, α2A, α2B, α2C, have been identified from multiple species. Because of the lack of sufficiently subtype-selective ligands, the specific biological functions of these receptor subtypes were largely unknown until recently. Gene-targeted mice carrying deletions in the genes encoding for individual α2-receptor subtypes have added important new insight into the physiological significance of adrenergic receptor diversity. Two different strategies have emerged to regulate adrenergic signal transduction. Some biological functions are controlled by two counteracting α2-receptor subtypes, e.g., α2A-receptors decrease sympathetic outflow and blood pressure, whereas the α2B-subtype increases blood pressure. Other biological functions are regulated by synergistic α2-receptor subtypes. The inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves also requires two receptor subtypes, α2A and α2C. Similarly, nociception is controlled at several levels by one of the three α2-receptor subtypes. Further investigation of the specific function of α2-subtypes will greatly enhance our understanding of the relevance of closely related receptor proteins and point out novel therapeutic strategies for subtype-selective drug development.
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Barbato, John C. "Estrogen Receptor Activation—Good, Aldosterone Receptor Blockade—Beneficial, Communication Between Receptors…Priceless." Hypertension 50, no. 2 (August 2007): 297–98. http://dx.doi.org/10.1161/hypertensionaha.107.092437.
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Maggi, Carlo Alberto, Riccardo Patacchini, Paolo Rovero, and Antonio Giachetti. "Tachykinin receptors and tachykinin receptor antagonists." Journal of Autonomic Pharmacology 13, no. 1 (February 1993): 23–93. http://dx.doi.org/10.1111/j.1474-8673.1993.tb00396.x.
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Gottlieb, Bruce, Lenore K. Beitel, Jianhui Wu, Youssef A. Elhaji, and Mark Trifiro. "Nuclear receptors and disease: androgen receptor." Essays in Biochemistry 40 (June 1, 2004): 121–36. http://dx.doi.org/10.1042/bse0400121.
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The androgen receptor (AR) protein regulates transcription of certain genes. Usually this depends upon a central DNA-binding domain that permits the binding of androgen–AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal ligand-binding domain and an Nterminal transcription modulatory domain. These N- and C-terminal domains interact directly, and with co-regulatory, non-receptor proteins, to exert precise control over a gene’s transcription rate. The precise roles of these proteins are active research areas. Severe X-linked AR gene (AR) mutations cause complete androgen insensitivity, mild ones impair virilization with or without infertility, and moderate ones yield a wide phenotypic spectrum sometimes among siblings. Different phenotype expressivity may reflect variability of ARinteractive proteins. Mutations occur throughout the AR but are concentrated in specific areas of the gene known as hot spots. A number of these mutations of somatic origin are associated with prostate cancer. N-terminal polyglutamine (polyGln) tract expansion reduces AR transactivation, and when there are more than 38 glutamine residues it causes spinobulbar muscular atrophy, a motor neuron disease, due to a gain of function. Variations in polyGln tract length have been associated as risk factors with prostate, breast, uterine, endometrial and colorectal cancer, as well as male infertility.
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Hall, Randy A. "Olfactory Receptor Interactions with Other Receptors." Annals of the New York Academy of Sciences 1170, no. 1 (July 2009): 147–49. http://dx.doi.org/10.1111/j.1749-6632.2009.03879.x.
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Oliver, Kevin R., Anna Wainwright, Lars Edvinsson, John D. Pickard, and Raymond G. Hill. "Immunohistochemical Localization of Calcitonin Receptor–Like Receptor and Receptor Activity–Modifying Proteins in the Human Cerebral Vasculature." Journal of Cerebral Blood Flow & Metabolism 22, no. 5 (May 2002): 620–29. http://dx.doi.org/10.1097/00004647-200205000-00014.
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Calcitonin gene-related peptide and adrenomedullin belong to a structurally related neuropeptide family and are potent vasodilators expressed in the trigeminovascular system. The molecular identity of receptors for these proteins has only recently been elucidated. Central to functional binding of these neuropeptides is the G-protein–coupled receptor, the calcitonin receptor–like receptor (CRLR), whose cell surface expression and pharmacology is determined by coexpression of a receptor activity-modifying protein (RAMP). CRLR combined with RAMP1 binds calcitonin gene-related peptide with high affinity, whereas CRLR coexpression with RAMP2 or −3 confers high-affinity binding of adrenomedullin. The authors investigated the expression of these receptor components in human cerebral vasculature to further characterize neuropeptide receptor content and the potential functions of these receptors. Localization has been carried out using specific antisera raised against immunogenic peptide sequences that were subsequently applied using modern immunohistochemical techniques and confocal microscopy. The results are the first to show the presence of these receptor component proteins in human middle meningeal, middle cerebral, pial, and superficial temporal vessels, and confirm that both calcitonin gene-related peptide and adrenomedullin receptors may arise from the coassembly of RAMPs with CRLR in these vessel types. These novel data advance the understanding of the molecular function of the trigeminovascular system, its potential role in vascular headache disorders such as migraine, and may lead to possible ways in which future synthetic ligands may be applied to manage these disorders.
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Rao, Rammohan V., Eileen L. Holicky, Susan M. Kuntz, and Laurence J. Miller. "CCK receptor phosphorylation exposes regulatory domains affecting phosphorylation and receptor trafficking." American Journal of Physiology-Cell Physiology 279, no. 6 (December 1, 2000): C1986—C1992. http://dx.doi.org/10.1152/ajpcell.2000.279.6.c1986.
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Agonist-stimulated phosphorylation of guanine nucleotide-binding protein (G protein)-coupled receptors has been recognized as an important mechanism for desensitization by interfering with coupling of the activated receptor with its G protein. We recently described a mutant of the CCK receptor that modified two of five key sites of phosphorylation (S260,264A) and eliminated agonist-stimulated receptor phosphorylation, despite normal ligand binding and signaling (20). As expected, this nonphosphorylated mutant had impaired rapid desensitization but was ultimately able to be desensitized by normal receptor internalization. Here we demonstrate that this mutant receptor is also defective in resensitization, with abnormal recycling to the cell surface. To explore this, another receptor mutant was prepared, replacing the same serines with aspartates to mimic the charge of serine-phosphate (S260,264D). This mutant was expressed in a Chinese hamster ovary cell line and shown to bind CCK normally. It had accelerated kinetics of signaling and desensitization and was phosphorylated in response to agonist occupation, with all other normal sites of phosphorylation modified. It was internalized like wild-type receptors and was resensitized and trafficked normally. This provides evidence for an additional important function for phosphorylation of G protein-coupled receptors. Phosphorylation may induce a conformational change in the receptor to expose other potential sites of phosphorylation and to expose domains involved in the targeting and trafficking of endosomes. The hierarchical phosphorylation of these sites may play a key role in receptor regulation.
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Ide, Hiroki, and Hiroshi Miyamoto. "Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor." Disease Markers 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/840640.
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There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression.
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Chauvin, Stephanie, Margaret Bencsik, Tom Bambino, and Robert A. Nissenson. "Parathyroid Hormone Receptor Recycling: Role of Receptor Dephosphorylation and β-Arrestin." Molecular Endocrinology 16, no. 12 (December 1, 2002): 2720–32. http://dx.doi.org/10.1210/me.2002-0049.
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Abstract The recovery of PTH receptor (PTHR) function after acute homologous receptor desensitization and down-regulation in bone and kidney cells has been attributed to receptor recycling. To determine the role of receptor dephosphorylation in PTHR recycling, we performed morphological and functional assays on human embryonic kidney 293 cells stably expressing wild-type (wt) or mutant PTHRs. Confocal microscopy and ligand binding assays revealed that the wt PTHR is rapidly recycled back to the plasma membrane after removal of the agonist. Receptors that were engineered to either lack the sites of phosphorylation or to resemble constitutively phosphorylated receptors were able to recycle back to the plasma membrane with the same kinetics as the wt PTHR. The PTHR was found to be dephosphorylated by an enzyme apparently distinct from protein phosphatases 1 or 2A. The PTHR and β-arrestin-2-green fluorescent protein (GFP) were found to stably colocalize during PTHR internalization, whereas after agonist removal and during receptor recycling, the colocalization slowly disappeared. Experiments using phosphorylation-deficient PTHRs and a dominant-negative form of β-arrestin showed that β-arrestin does not regulate the efficiency of PTHR recycling. These studies indicate that, unlike many G protein-coupled receptors, PTHR recycling does not require receptor dephosphorylation or its dissociation from β-arrestin.
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Qian, Hongwei, Luisa Pipolo, and Walter G. Thomas. "Association of β-Arrestin 1 with the Type 1A Angiotensin II Receptor Involves Phosphorylation of the Receptor Carboxyl Terminus and Correlates with Receptor Internalization." Molecular Endocrinology 15, no. 10 (October 1, 2001): 1706–19. http://dx.doi.org/10.1210/mend.15.10.0714.
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Abstract Arrestins bind to phosphorylated G protein-coupled receptors and participate in receptor desensitization and endocytosis. Although arrestins traffic with activated type 1 (AT1A) angiotensin II (AngII) receptors, the contribution of arrestins to AT1A receptor internalization is controversial, and the physical association of arrestins with the AT1A receptor has not been established. In this study, by coimmunoprecipitating AT1A receptors and β-arrestin 1, we provide direct evidence for an association between arrestins and the AT1A receptor that was agonist- and time-dependent and contingent upon the level ofβ -arrestin 1 expression. Serial truncation of the receptor carboxyl terminus resulted in a graded loss of β-arrestin 1 association, which correlated with decreases in receptor phosphorylation. Truncation of the AT1A receptor to lysine325 prevented AngII-induced phosphorylation and β-arrestin 1 association as well as markedly inhibiting receptor internalization, indicating a close correlation between these receptor parameters. AngII-induced association was also dramatically reduced in a phosphorylation- and internalization-impaired receptor mutant in which four serine and threonine residues in the central portion of the AT1A receptor carboxyl terminus (Thr332, Ser335, Thr336, Ser338) were substituted with alanine. In contrast, substitutions in another serine/threonine-rich region (Ser346, Ser347, Ser348) and at three PKC phosphorylation sites (Ser331, Ser338, Ser348) had no effect on AngII-inducedβ -arrestin 1 association or receptor internalization. While AT1A receptor internalization could be inhibited by a dominant-negative β-arrestin 1 mutant (βarr1319–418), treatment with hyperosmotic sucrose to inhibit internalization did not abrogate the differences in arrestin association observed between the wild-type and mutant receptors, indicating that arrestin binding precedes, and is not dependent upon, receptor internalization. Interestingly, a substituted analog of AngII,[ Sar1Ile4Ile8]-AngII, which promotes robust phosphorylation of the receptor but does not activate receptor signaling, stimulated strong β-arrestin 1 association with the full-length AT1A receptor. These results identify the central portion of the AT1A receptor carboxyl terminus as the important determinant for β-arrestin 1 binding and internalization and indicate that AT1A receptor phosphorylation is crucial for β-arrestin docking.
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Salmon, J. E., N. Brogle, C. Brownlie, J. C. Edberg, R. P. Kimberly, B. X. Chen, and B. F. Erlanger. "Human mononuclear phagocytes express adenosine A1 receptors. A novel mechanism for differential regulation of Fc gamma receptor function." Journal of Immunology 151, no. 5 (September 1, 1993): 2775–85. http://dx.doi.org/10.4049/jimmunol.151.5.2775.
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Abstract Using monoclonal anti-adenosine A1 receptor antibodies that bind the A1 receptor ligand binding site, we demonstrate that A1 receptors are expressed on cultured monocytes and rheumatoid synovial fluid mononuclear phagocytes. This finding is associated with the acquisition of reactivity with selective adenosine A1 receptor agonists and is temporally coordinated with the induction of adenosine A2 receptors on cultured monocytes. In a rapid, concentration-dependent fashion, these two distinct adenosine receptors modulate Fc gamma receptor-mediated phagocytosis, a response critical to the pathogenesis of immune complex diseases. Occupancy of A1 receptors by N6-cyclopentyladenosine (an A1-specific adenosine analogue) or mAb AA1 (an anti-A1 mAb) results in a potent stimulation that is blocked by adenosine receptor antagonists. This A1 receptor-induced enhancement of Fc gamma receptor-mediated phagocytosis is a consequence of preferential augmentation of Fc gamma RI function, suggesting distinct mechanisms for receptor-effector coupling of Fc gamma receptor families. In contrast, ligation of A2 receptors by A2-specific agonists decreases Fc gamma receptor-mediated phagocytosis in cultured monocytes. The opposing effects of adenosine A1 and A2 receptors allow for a concentration-dependent feed-back loop that responds more rapidly than effects elicited by other endogenous modulators. Low concentrations of adenosine are proinflammatory providing enhanced Fc gamma receptor function via A1 receptors, whereas higher concentrations that can occur with tissue damage are anti-inflammatory providing inhibition via A2 receptors. This rapid and potent modulation of Fc gamma receptor-mediated function suggests that adenosine is an important local regulator of the inflammatory response.
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Hammond-Weinberger, Dena R., Yunxin Wang, Alex Glavis-Bloom, and Nicholas C. Spitzer. "Mechanism for neurotransmitter-receptor matching." Proceedings of the National Academy of Sciences 117, no. 8 (February 10, 2020): 4368–74. http://dx.doi.org/10.1073/pnas.1916600117.
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Synaptic communication requires the expression of functional postsynaptic receptors that match the presynaptically released neurotransmitter. The ability of neurons to switch the transmitter they release is increasingly well documented, and these switches require changes in the postsynaptic receptor population. Although the activity-dependent molecular mechanism of neurotransmitter switching is increasingly well understood, the basis of specification of postsynaptic neurotransmitter receptors matching the newly expressed transmitter is unknown. Using a functional assay, we show that sustained application of glutamate to embryonic vertebrate skeletal muscle cells cultured before innervation is necessary and sufficient to up-regulate ionotropic glutamate receptors from a pool of different receptors expressed at low levels. Up-regulation of these ionotropic receptors is independent of signaling by metabotropic glutamate receptors. Both imaging of glutamate-induced calcium elevations and Western blots reveal ionotropic glutamate receptor expression prior to immunocytochemical detection. Sustained application of glutamate to skeletal myotomes in vivo is necessary and sufficient for up-regulation of membrane expression of the GluN1 NMDA receptor subunit. Pharmacological antagonists and morpholinos implicate p38 and Jun kinases and MEF2C in the signal cascade leading to ionotropic glutamate receptor expression. The results suggest a mechanism by which neuronal release of transmitter up-regulates postsynaptic expression of appropriate transmitter receptors following neurotransmitter switching and may contribute to the proper expression of receptors at the time of initial innervation.
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Pellas, Theodore C., and Lawrence P. Wennogle. "CSa Receptor Antagonists." Current Pharmaceutical Design 5, no. 10 (October 1999): 737–55. http://dx.doi.org/10.2174/1381612805666230111205710.
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The anaphylatoxin C5a is an extremely potent proinflammatory peptide produced during activation of the complement system. The structure of C5a includes a 'core' region (N-terminal residues 1-63) consisting of four, antiparallel alpha helices held together by three disulfide linkages and a structured C-terminal 'tail' (residues 64-74). The C5a receptor belongs to the large class of seven transmembrane, G-protein-linked receptors. C5a appears to interact with its receptor at two sites: the C5a core binds to the receptor's N-terminal extracellular domain while C5a's tail binds the receptor near Arg206, near the membrane surface of transmembrane helix V. C5a receptors are concentrated on blood granulocytes (neutrophils, eosinophils, and basophils) and tissue inflammatory cells (macrophages, mast cells, microglia); thus the main effects of C5a are manifest as inflammation. Additionally, C5a receptors are also present, albeit in lower concentrations, on non-myeloid cells, e.g. endothelial and smooth muscle cells where they may further influence inflammatory reactions such as blood cell emigration and tissue edema. C5a has been implicated in myriad disorders, both acute and chronic; therefore a C5a receptor antagonist is predicted to have utility as a therapeutic agent. Unfortunately, few specific C5a receptor antagonists have been reported, and only two have demonstrated activity in vivo. Furthermore, those reported are peptidic and hence have limited application therapeutically. The current state of C5a receptor antagonists is discussed as well as the potential for their use against various human disorders. A model of C5a receptor dimerization is presented to account for the high potency of the disulfide antagonist C5aRAD.
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Jezova, Miroslava, Ines Armando, Claudia Bregonzio, Zu-Xi Yu, Sujuan Qian, Victor J. Ferrans, Hans Imboden, and Juan M. Saavedra. "Angiotensin II AT1 and AT2 Receptors Contribute to Maintain Basal Adrenomedullary Norepinephrine Synthesis and Tyrosine Hydroxylase Transcription." Endocrinology 144, no. 5 (May 1, 2003): 2092–101. http://dx.doi.org/10.1210/en.2002-0019.
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Angiotensin II (Ang II) AT1 receptors have been proposed to mediate the Ang II-dependent and the stress-stimulated adrenomedullary catecholamine synthesis and release. However, in this tissue, most of the Ang II receptors are of the AT2 type. We asked the question whether AT1 and AT2 receptors regulate basal catecholamine synthesis. Long-term AT1 receptor blockade decreased adrenomedullary AT1 receptor binding, AT2 receptor binding and AT2 receptor protein, rat tyrosine hydroxylase (TH) mRNA, norepinephrine (NE) content, Fos-related antigen 2 (Fra-2) protein, phosphorylated cAMP response element binding protein (pCREB), and ERK2. Long-term AT2 receptor blockade decreased AT2 receptor binding, TH mRNA, NE content and Fra-2 protein, although not affecting AT1 receptor binding or receptor protein, pCREB or ERK2. Angiotensin II colocalized with AT1 and AT2 receptors in ganglion cell bodies. AT2 receptors were clearly localized to many, but not all, chromaffin cells. Our data support the hypothesis of an AT1/AT2 receptor cross-talk in the adrenomedullary ganglion cells, and a role for both receptor types on the selective regulation of basal NE, but not epinephrine formation, and in the regulation of basal TH transcription. Whereas AT1 and AT2 receptors involve the Fos-related antigen Fra-2, AT1 receptor transcriptional effects include pCREB and ERK2, indicating common as well as different regulatory mechanisms for each receptor type.
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Stengel, Peter W., Masahisa Yamada, Jürgen Wess, and Marlene L. Cohen. "M3-receptor knockout mice: muscarinic receptor function in atria, stomach fundus, urinary bladder, and trachea." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 282, no. 5 (May 1, 2002): R1443—R1449. http://dx.doi.org/10.1152/ajpregu.00486.2001.
Full textAbstract:
Negative chronotropic and smooth muscle contractile responses to the nonselective muscarinic agonist carbamylcholine were compared in isolated tissues from M3-muscarinic receptor knockout and wild-type mice. Carbamylcholine (10−8–3.0 × 10−5 M) induced a concentration-dependent decrease in atrial rate that was similar in atria from M3-receptor knockout and wild-type mice, indicating that M3 receptors were not involved in muscarinic receptor-mediated atrial rate decreases. In contrast, the M3 receptor was a major muscarinic receptor involved in smooth muscle contraction of stomach fundus, urinary bladder, and trachea, although differences existed in the extent of M3-receptor involvement among the tissues. Contraction to carbamylcholine was virtually abolished in urinary bladder from M3-receptor knockout mice, suggesting that contraction was predominantly due to M3-receptor activation. However, ∼50–60% maximal contraction to carbamylcholine occurred in stomach fundus and trachea from M3-receptor knockout mice, indicating that contraction in these tissues was also due to M2-receptor activation. High concentrations of carbamylcholine relaxed the stomach fundus from M3-receptor knockout mice by M1-receptor activation. Thus M3-receptor knockout mice provided unambiguous evidence that M3 receptors 1) play no role in carbamylcholine-induced atrial rate reduction, 2) are the predominant receptor mediating carbamylcholine-induced urinary bladder contractility, and 3) share contractile responsibility with M2 receptors in mouse stomach fundus and trachea.
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Blake, A. D., N. S. Hayes, E. E. Slater, and C. D. Strader. "Insulin receptor desensitization correlates with attenuation of tyrosine kinase activity, but not of receptor endocytosis." Biochemical Journal 245, no. 2 (July 15, 1987): 357–64. http://dx.doi.org/10.1042/bj2450357.
Full textAbstract:
A model of insulin-receptor down-regulation and desensitization has been developed and described. In this model, both insulin-receptor down-regulation and functional desensitization are induced in the human HepG2 cell line by a 16 h exposure of the cells to 0.1 microM-insulin. Insulin-receptor affinity is unchanged, but receptor number is decreased by 50%, as determined both by 125I-insulin binding and by protein immunoblotting with an antibody to the beta-subunit of the receptor. This down-regulation is accompanied by a disproportionate loss of insulin-stimulated glycogen synthesis, yielding a population of cell-surface insulin receptors which bind insulin normally but which are unable to mediate insulin-stimulated glycogen synthesis within the cell. Upon binding of insulin, the desensitized receptors are internalized rapidly, with characteristics indistinguishable from those of control cells. In contrast, this desensitization is accompanied by a loss of the insulin-sensitive tyrosine kinase activity of insulin receptors isolated from these cells. Receptors isolated from control cells show a 5-25-fold enhancement of autophosphorylation of the beta-subunit by insulin; this insulin-responsive autophosphorylation is severely attenuated after desensitization to a maximum of 0-2-fold stimulation by insulin. Likewise, the receptor-mediated phosphorylation of exogenous angiotensin II, which is stimulated 2-10-fold by insulin in receptors from control cells, is completely unresponsive to insulin in desensitized cells. These data provide evidence that the insulin-receptor tyrosine kinase activity correlates with insulin stimulation of an intracellular metabolic event. The data suggest that receptor endocytosis is not sufficient to mediate insulin's effects, and thereby argue for a role of the receptor tyrosine kinase activity in the mediation of insulin action.
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Kiely, J., J. R. Hadcock, S. W. Bahouth, and C. C. Malbon. "Glucocorticoids down-regulate β1-adrenergic-receptor expression by suppressing transcription of the receptor gene." Biochemical Journal 302, no. 2 (September 1, 1994): 397–403. http://dx.doi.org/10.1042/bj3020397.
Full textAbstract:
The expression of beta 2-adrenergic receptors is up-regulated by glucocorticoids. In contrast, beta 1-adrenergic receptors display glucocorticoid-induced down-regulation. In rat C6 glioma cells, which express both of these subtypes of beta-adrenergic receptors, the synthetic glucocorticoid dexamethasone stimulates no change in the total beta-adrenergic receptor content, but rather shifts the beta 1:beta 2 ratio from 80:20 to 50:50. Radioligand binding and immunoblotting demonstrate a sharp decline in beta 1-adrenergic receptor expression. Metabolic labelling of cells with [35S]-methionine in tandem with immunoprecipitation by beta 1-adrenergic-receptor-specific antibodies reveals a sharp decline in the synthesis of the receptor within 48 h for cells challenged with glucocorticoid. Steady-state levels of beta 1-adrenergic-receptor mRNA declined from 0.47 to 0.26 amol/microgram of total cellular RNA within 2 h of dexamethasone challenge, as measured by DNA-excess solution hybridization. The stability of receptor mRNA was not influenced by glucocorticoid; the half-lives of the beta 1- and beta 2-subtype mRNAs were 1.7 and 1.5 h respectively. Nuclear run-on assays revealed the basis for the down-regulation of receptor expression, i.e. a sharp decline in the relative rate of transcription for the beta 1-adrenergic-receptor gene in nuclei from dexamethasone-treated as compared with vehicle-treated cells. These data demonstrate transcriptional suppression as a molecular explanation for glucocorticoid-induced down-regulation of beta 1-adrenergic receptors.