Showing papers on "Receptor published in 1990"
TL;DR: The molecular mechanisms underlying rapid βAR desensitization do not appear to require internalization of the receptors, but rather an alteration in the functioning of βAR themselves that uncouples the receptors from the stimulatory G protein Gs.
Abstract: Cellular responses to many hormones and neurotransmitters wane rapidly despite continuous exposure of cells to these stimuli. This phenomenon, termed desensitization, has been particularly well studied for the stimulation of cAMP levels by plasma membrane beta-adrenergic receptors (beta AR). The molecular mechanisms underlying rapid beta AR desensitization do not appear to require internalization of the receptors, but rather an alteration in the functioning of beta AR themselves that uncouples the receptors from the stimulatory G protein Gs. This uncoupling phenomenon involves phosphorylation of beta AR by at least two kinases, PKA and the beta AR kinase (beta ARK), which are activated under different desensitizing conditions. Receptor phosphorylation by the two kinases leads to desensitization of the receptor response via distinct biochemical mechanisms, and additional cytosolic factors appear to be involved in the case of beta ARK. Numerous experimental approaches have been used recently to elucidate th...
1,286 citations
TL;DR: It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors.
Abstract: Homologous or agonist-specific desensitization of beta-adrenergic receptors is thought to be mediated by a specific kinase, the beta-adrenergic receptor kinase (beta ARK). However, recent data suggest that a cofactor is required for this kinase to inhibit receptor function. The complementary DNA for such a cofactor was cloned and found to encode a 418-amino acid protein homologous to the retinal protein arrestin. The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors.
1,185 citations
TL;DR: Northern analysis indicates a single species of mRNA for the TNF-R in a variety of cell types, therefore, the soluble TNF binding protein found in human serum is probably proteolytically derived from the T NF-R.
1,163 citations
TL;DR: Three interleukin-1 inhibitors have been purified to homogeneity from medium conditioned by human monocytes and partial sequence analysis and digestion with N-glycanase indicate that these are glycosylation forms of a single protein.
Abstract: Three interleukin-1 inhibitors have been purified to homogeneity from medium conditioned by human monocytes. Partial sequence analysis and digestion with N-glycanase indicate that these are glycosylation forms of a single protein. The protein binds to the interleukin-1 receptor but has no interleukin-1-like activity, even at very high concentrations, and is therefore a pure receptor antagonist.
1,153 citations
TL;DR: The predicted cysteine-rich extracellular domain has extensive sequence similarity with five proteins, including nerve growth factor receptor and a transcriptionally active open reading frame from Shope fibroma virus, and thus defines a family of receptors.
Abstract: Tumor necrosis factor alpha and beta (TNF-alpha and TNF-beta) bind surface receptors on a variety of cell types to mediate a wide range of immunological responses, inflammatory reactions, and anti-tumor effects. A cDNA clone encoding an integral membrane protein of 461 amino acids was isolated from a human lung fibroblast library by direct expression screening with radiolabeled TNF-alpha. The encoded receptor was also able to bind TNF-beta. The predicted cysteine-rich extracellular domain has extensive sequence similarity with five proteins, including nerve growth factor receptor and a transcriptionally active open reading frame from Shope fibroma virus, and thus defines a family of receptors.
1,142 citations
TL;DR: Two distinct receptors for tumor necrosis factor (TNF) of 55 and 75 kd were expressed at low levels by various cells as discussed by the authors, and partial amino acid sequences were determined Short degenerate sense and antisense oligonucleotide primers encoding the N- and C-terminal ends of a peptide of 22 amino acid residues were used to amplify a 66 bp cDNA fragment from HL60 RNA by reverse transcriptase-polymerase chain reaction.
1,048 citations
TL;DR: In the LNCaP androgen receptor a single point mutation is discovered changing the sense of codon 868 (Thr to Ala) in the ligand binding domain, which influences both binding and the induction of gene expression by different steroids and antisteroids.
1,002 citations
TL;DR: Subpopulations of GABAA receptors with different cellular and regional locations show differential sensitivity to GABA, to modulators like steroids, to physiological regulation, to disease processes, and to pharmacological manipulation by drugs such as benzodiazepines.
Abstract: The major type of receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), called the GABAA receptor, is a member of a gene superfamily of ligand-gated ion channels. This receptor is a hetero-oligomeric protein composed of several distinct polypeptide types (alpha, beta, gamma, and delta). Molecular cloning of these polypeptides reveals that they show 20-40% identity with each other, and 10-20% identity with polypeptides of the nicotinic acetylcholine receptors and strychnine-sensitive glycine receptor. Each polypeptide type is also represented by a family of genes whose members have 60-80% amino acid sequence identity. Regions of conserved and variable amino acid sequence suggest structural and functional domains within each polypeptide. All of the polypeptides when expressed in heterologous cells produce GABA-activated chloride channels, and the different subtypes express different pharmacological properties. The distributions of mRNAs for the different GABAA receptor polypeptides and their subtypes show significant brain regional variation consistent with pharmacological and biochemical evidence for receptor heterogeneity. Subpopulations of GABAA receptors with different cellular and regional locations show differential sensitivity to GABA, to modulators like steroids, to physiological regulation, to disease processes, and to pharmacological manipulation by drugs such as benzodiazepines. The properties of the different subpopulations of GABAA receptors are determined by which one or more of the different polypeptides and their subtypes are expressed in a given cell to produce a variety of different oligomeric protein structures. Molecular cloning techniques have produced rapid advances in understanding the GABAA receptor protein family.
971 citations
TL;DR: A review of published data revealed NPXY sequences in cytoplasmic domains of at least 10 other cell surface proteins, including tyrosine kinase-linked receptors of the epidermal growth factor and insulin receptor family, the beta-subunits of three integrin receptors, and the amyloid A4 precursor protein.
952 citations
TL;DR: Three closely related genes encode receptor subunits for the excitatory neurotransmitter glutamate as discussed by the authors, which form homomeric ion channels in Xenopus oocytes that are sensitive to glutamatergic agonists such as kainate and quisqualate but not to N-methyl-D-aspartate.
Abstract: Three closely related genes, GluR1, GluR2, and GluR3, encode receptor subunits for the excitatory neurotransmitter glutamate. The proteins encoded by the individual genes form homomeric ion channels in Xenopus oocytes that are sensitive to glutamatergic agonists such as kainate and quisqualate but not to N-methyl-D-aspartate, indicating that binding sites for kainate and quisqualate exist on single receptor polypeptides. In addition, kainate-evoked conductances are potentiated in oocytes expressing two or more of the cloned receptor subunits. Electrophysiological responses obtained with certain subunit combinations show agonist profiles and current-voltage relations that are similar to those obtained in vivo. Finally, in situ hybridization histochemistry reveals that these genes are transcribed in shared neuroanatomical loci. Thus, as with gamma-aminobutyric acid, glycine, and nicotinic acetylcholine receptors, native kainate-quisqualate-sensitive glutamate receptors form a family of heteromeric proteins.
941 citations
TL;DR: It is concluded that ICAM-1 is a counter receptor for Mac-1 and that this receptor pair is responsible, in part, for the adhesion between stimulated neutrophils and stimulated endothelial cells.
Abstract: While the leukocyte integrin lymphocyte function-associated antigen (LFA)-1 has been demonstrated to bind intercellular adhesion molecule (ICAM)-1, results with the related Mac-1 molecule have been controversial. We have used multiple cell binding assays, purified Mac-1 and ICAM-1, and cell lines transfected with Mac-1 and ICAM-1 cDNAs to examine the interaction of ICAM-1 with Mac-1. Stimulated human umbilical vein endothelial cells (HUVECs), which express a high surface density of ICAM-1, bind to immunoaffinity-purified Mac-1 adsorbed to artificial substrates in a manner that is inhibited by mAbs to Mac-1 and ICAM-1. Transfected murine L cells or monkey COS cells expressing human ICAM-1 bind to purified Mac-1 in a specific and dose-dependent manner; the attachment to Mac-1 is more temperature sensitive, lower in avidity, and blocked by a different series of ICAM-1 mAbs when compared to LFA-1. In a reciprocal assay, COS cells cotransfected with the alpha and beta chain cDNAs of Mac-1 or LFA-1 attach to immunoaffinity-purified ICAM-1 substrates; this adhesion is blocked by mAbs to ICAM-1 and Mac-1 or LFA-1. Two color fluorescence cell conjugate experiments show that neutrophils stimulated with fMLP bind to HUVEC stimulated with lipopolysaccharide for 24 h in an ICAM-1-, Mac-1-, and LFA-1-dependent fashion. Because cellular and purified Mac-1 interact with cellular and purified ICAM-1, we conclude that ICAM-1 is a counter receptor for Mac-1 and that this receptor pair is responsible, in part, for the adhesion between stimulated neutrophils and stimulated endothelial cells.
TL;DR: It is reported that macrophage recognition of apoptotic cells (both neutrophils and lymphocytes) is mediated by the vitronectin receptor, a heterodimer belonging to the β3 or cytoadhesin family of the integrins.
Abstract: PHAGOCYTE recognition of cells that have undergone apoptosis (programmed cell death) is an event of broad biological significance. Characterized by endogenous endonuclease activation1, which results in chromatin fragmentation and nuclear condensation2, apoptosis leads to swift ingestion of intact but 'senescent' or 'unwanted' cells by phagocytes in processes as diverse as the physiological involution of organs, the remodelling of embryonic tissues, and metamorphosis3. The cell-surface mechanisms by which macrophages recognize apoptotic cells as 'senescent-self' have remained obscure. Here we report that macrophage recognition of apoptotic cells (both neutrophils and lymphocytes) is mediated by the vitronectin receptor, a heterodimer belonging to the β3 or cytoadhesin family of the integrins4–9. Previously, the functions of the vitronectin receptor were believed to be limited to cell anchorage10–12, but our findings indicate that the receptor has a novel and direct role in self–senescent-self intercellular recognition leading to macrophage phagocytosis of cells undergoing apoptosis.
TL;DR: There is a consensus that one major function is to inactivate receptor by blocking DNA binding, and posttranslational modifications such as phosphorylation have been postulated to modulate several functional properties of steroid receptors.
Abstract: Steroid receptors are a class of molecules that function as both signal transducers and transcription factors. From cloned sequences it is apparent that steroid receptors and other transcription factors belong to a superfamily of proteins that appear to function by similar mechanisms. Functional domains for hormone and DNA binding, and for transcriptional activation, have been defined for several receptors. In some cases, specific amino acids required for function have been identified. The multi-functional steroid receptor molecules are modular in nature in that domains function independently of structural position in receptor molecules and can even function after insertion into unrelated transactivation proteins. The mechanism of receptor action is complex and multistage and a number of unanswered questions remain to be defined. Receptors are inactive in the absence of hormone in vivo; the proposed components of this inactive complex include several proteins and RNA. Theories on the physiological role of HSP 90 in this complex range from an artifactual interaction to an absolute conformational requirement for hormone binding. Although its function has not been demonstrated clearly yet, there is a consensus that one major function is to inactivate receptor by blocking DNA binding. Most of the steroid receptors appear to be nuclear in the absence of hormone. The transformation process produces a receptor molecule that is capable of specific DNA binding and transcriptional activation. The specificity of DNA binding is conferred by as few as three amino acids in the first finger of the C1 region. Receptors appear to bind to DNA as dimers although whether dimers are preformed in cytoplasm remains unknown. Although the DNA binding domain is required for gene activation, other regions of the molecule in the carboxyl and amino terminus enhance activation function. Important interactions of steroid receptors with other receptors and unrelated transcription factors has been proposed and most certainly occurs. Finally, posttranslational modifications such as phosphorylation have been postulated to modulate several functional properties of steroid receptors.
TL;DR: Binding was not detected on 3T3 fibroblasts carrying the steel (Sl) mutation, confirming the biological significance of the binding activity and demonstrating that mutations at the Sl locus affect the expression or structure of the kit ligand.
TL;DR: This work has taken advantage of the capacity of mammalian steroid receptors to function in yeast and constructed a strain of Saccharomyces cerevisiae in which hsp90 expression was regulatable and could be reduced more than 20-fold relative to wild type, providing the first biological evidence that hSp90 acts in the signal transduction pathway for steroid receptors.
Abstract: Signalling by steroid hormones is mediated by receptor proteins that bind hormonal ligands and regulate the transcription of specific genes. The heat-shock protein hsp90 seems to associate selectively with unliganded receptors (aporeceptors), but it has not been determined whether this interaction affects receptor function in vivo. To address the role of hsp90, we have taken advantage of the capacity of mammalian steroid receptors to function in yeast. We constructed a strain of Saccharomyces cerevisiae in which hsp90 expression was regulatable and could be reduced more than 20-fold relative to wild type. At low levels of hsp90, aporeceptors seem to be mostly hsp90-free, yet fail to enhance transcription; on hormone addition, the receptors are activated but with markedly reduced efficiency. Thus hsp90 does not inhibit receptor function solely by steric interference; rather, hsp90 seems to facilitate the subsequent response of the aporeceptor to the hormonal signal. This is the first biological evidence that hsp90 acts in the signal transduction pathway for steroid receptors.
TL;DR: It is demonstrated that the agonistic effect of OHT on the whole hER is due to the cell‐type and promoter‐context dependent activity of TAF‐1, and it is confirmed that the wild type human oestrogen receptor has no ligand independent transcriptional activity.
Abstract: Various oestrogen responsive reporter genes and vectors expressing truncated or chimeric human oestrogen receptors (hER) containing either of the two independent hER transcriptional activation functions (TAF-1 and TAF-2) have been transfected into HeLa cells, chicken embryo fibroblast (CEF) or yeast cells to investigate the agonistic activity of the anti-oestrogen 4-hydroxytamoxifen (OHT). We demonstrate that the agonistic effect of OHT on the whole hER is due to the cell-type and promoter-context dependent activity of TAF-1. In similar experiments, we show that the anti-oestrogen, ICI 164,384, does not exhibit any oestrogenic activity and, therefore, acts always as a pure antagonist, even though it does not inhibit the activity of the isolated TAF-1. We also confirm that the wild type human oestrogen receptor has no ligand independent transcriptional activity. The implications of our results for the variable antagonist/agonist activity of anti-oestrogens in vivo are discussed.
TL;DR: It is shown here that multiple members of the integrin superfamily of cell adhesion receptors bind the Y. pseudotuberculosis invasin protein prior to bacterial penetration into mammalian cells.
TL;DR: Immunologic blot and immunoprecipitation analyses indicate that mAbs htr-9 and utr-1 recognize proteins of approximately 55 kDa and 75 kDa, respectively, which provide evidence for the existence of two distinct TNF receptor molecules that contribute to varying extent to the TNF binding by different human cells.
Abstract: The pleiotropic cyto/lymphokine tumor necrosis factor (TNF) exerts its functions by binding to specific cell-surface receptors. We have prepared two sets of monoclonal antibodies (mAbs) against TNF-binding proteins from the HL-60 (htr-mAb series) and U-937 (utr-mAb series) cell lines. The htr antibodies inhibit the binding of 125I-labeled TNF-alpha to HL-60 cells only partially, whereas they block the TNF-alpha binding to several adenocarcinoma cell lines (HEp-2, HeLa, and MCF7) almost completely. In contrast, the utr antibodies have no effect on TNF-alpha binding to the adenocarcinoma cell lines but partially inhibit TNF-alpha binding to HL-60 and U-937 cells. However, htr-9 and utr-1 antibodies in combination fully inhibit the TNF-alpha binding to HL-60 and U-937 cells. The binding of TNF-beta to HEp-2 and U-937 cells is also inhibited by htr and utr antibodies. Neither htr nor utr mAb has an effect on the TNF-sensitive murine cell lines L929 and WEHI 164. Flow cytometry studies show that mAbs htr-9 and utr-1 detect two distinct TNF-binding sites on human cell lines. Immunologic blot and immunoprecipitation analyses indicate that mAbs htr-9 and utr-1 recognize proteins of approximately 55 kDa and 75 kDa, respectively. These data provide evidence for the existence of two distinct TNF receptor molecules that contribute to varying extent to the TNF binding by different human cells.
TL;DR: In this article, the authors show that CD28 serves as the surface component of a novel signal transduction pathway that modulates T-cell lymphokine production and increases the resistance of T-cells responses to various immunosuppressive agents.
TL;DR: It is found that a 1000-fold excess of the heterologous ligand is needed to reduce binding to the high-affinity receptor by 50%, but that the same concentrations of BDNF and NGF similarly reduce the binding of either ligand to the low-Affinity receptor.
TL;DR: The mechanism of InsP, receptor action suggested here is shown to lead to a potential reconciliation of all these conflicting proposals on regulated Ca2+ entry and release.
TL;DR: A human myelomonocytic cell line, U937, produced an interleukin-1 (IL-1) receptor antagonist protein (IRAP) which was purified and partially sequenced and was a potent inhibitor of IL-1 induced corticosterone production in vivo.
Abstract: A human myelomonocytic cell line, U937, produced an interleukin-1 (IL-1) receptor antagonist protein (IRAP) which was purified and partially sequenced. A complementary DNA coding for IRAP was cloned and sequenced. The mature translation product of the cDNA has been expressed in Escherichia coli and was an active competitive inhibitor of the binding of IL-1 to the T-cell/fibroblast form of the IL-1 receptor. Recombinant IRAP specifically inhibited IL-1 bioactivity on T cells and endothelial cells in vitro and was a potent inhibitor of IL-1 induced corticosterone production in vivo.
TL;DR: The findings presented in this study are consistent with the notion that the urinary TNF-binding proteins constitute soluble forms of the two molecular species of the cell surface TNF receptors.
TL;DR: This review summarizes the current knowledge of the molecular mechanisms by which the GPC-Rs activate second messenger systems, and it addresses their regulation and structure.
Abstract: The G protein coupled receptors (GPC-Rs) comprise a large superfamily of genes encoding numerous receptors which all show common structural features, e.g., seven putative membrane spanning domains. Their biological functions are extremely diverse, ranging from vision and olfaction to neuronal and endocrine signaling. The GPC-Rs couple via multiple G proteins to a growing number of recognized second messenger pathway, e.g., cAMP and phosphatidyl inositol turnover. This review summarizes our current knowledge of the molecular mechanisms by which the GPC-Rs activate second messenger systems, and it addresses their regulation and structure.
TL;DR: The complete cDNA cloning of two human genes previously designated flg and bek is reported, indicating that bek and flg bind either aFGF or bFGF with dissociation constants of (2‐15) x 10(‐11) M.
Abstract: The fibroblast growth factor (FGF) family consists of at least seven closely related polypeptide mitogens which exert their activities by binding and activation of specific cell surface receptors. Unanswered questions have been whether there are multiple FGF receptors and what factors determine binding specificity and biological response. We report the complete cDNA cloning of two human genes previously designated flg and bek. These genes encode two similar but distinct cell surface receptors comprised of an extracellular domain with three immunoglobulin-like regions, a single transmembrane domain, and a cytoplasmic portion containing a tyrosine kinase domain with a typical kinase insert. The expression of these two cDNAs in transfected NIH 3T3 cells led to the biosynthesis of proteins of 150 kd and 135 kd for flg and bek, respectively. Direct binding experiments with radiolabeled acidic FGF (aFGF) or basic FGF (bFGF), inhibition of binding with native growth factors, and Scatchard analysis of the binding data indicated that bek and flg bind either aFGF or bFGF with dissociation constants of (2-15) x 10(-11) M. The high affinity binding of two distinct growth factors to each of two different receptors represents a unique double redundancy without precedence among polypeptide growth factor-receptor interactions.
TL;DR: It is demonstrated that basic FGF is a potent mitogen for brain O-2A progenitor cells, but blocks their differentiation into oligodendrocytes, which may modulate the production of myelin-forming cells in the CNS.
TL;DR: Analysis of the sequence of the IL-7 receptor revealed significant homology in the extracellular domain to several recently cloned cytokine receptors, demonstrating that the IL -7 receptor is a member of a new receptor superfamily.
TL;DR: Observations indicate that the kainate/quisqualate receptors are encoded by a family of genes and are likely to be composed of hetero-oligomers of at least two distinct subunits.
TL;DR: It is proposed that the function of CRBP is to store and release retinol where high levels of RA are required for specific morphogenetic processes, while CRABP serves to sequester RA in regions where normal developmental functions require RA levels to be low.
Abstract: We report here the gene expression patterns, as revealed by in situ hybridisation, of the retinoic acid receptors alpha, beta and gamma (RAR-alpha, -beta and -gamma), and the cellular binding proteins for retinol and retinoic acid (CRBP, CRABP) in non-neural tissues of mouse embryos during the period of organogenesis. At all stages, RAR-alpha transcripts were almost ubiquitous, whereas the distribution of transcripts of the other four genes was distinctive in all systems. At early stages in the formation of an organ, the expression patterns were different in the epithelium, the adjacent mesenchyme, and in mesenchyme more distant from the epithelium, suggesting a role for RA and RA receptors in epithelial-mesenchymal tissue interactions. In the developing face, limb bud and genital tubercle, where large expanses of mesenchyme are present, differential patterns of expression were established before the onset of overt tissue differentiation, suggesting some significance for pattern formation in these regions. The distribution of RAR-beta transcripts in tracheobronchial, intestinal and genital tract epithelial is consistent with the possibility that RAR-beta plays a role in mediating retinoid effects on the differentiated stage of these epithelia. Possible developmental roles of RARs in relation to the expression patterns of other genes are discussed. CRBP expression domains showed a high degree of overlap with RAR-beta and RAR-gamma, and a mutual exclusivity with CRABP expression domains. Correlation of these expression patterns with the morphogenetic effects of vitamin A deficiency and retinoid excess lead us to propose that the function of CRBP is to store and release retinol where high levels of RA are required for specific morphogenetic processes, while CRABP serves to sequester RA in regions where normal developmental functions require RA levels to be low. Where both binding protein genes are expressed in a non-overlapping pattern within a large area of mesenchyme, a gradient of free RA may be created between them by release of retinol-derived RA from CRBP-expressing cells, with binding to CRABP enhancing the steepness of the decline in concentration distant to the source.
TL;DR: Although many combinations of alpha beta T cell receptors are available to the T cells in any given organism, far fewer are actually used by mature T cells.
Abstract: Although many combinations of alpha beta T cell receptors are available to the T cells in any given organism, far fewer are actually used by mature T cells. The combinations used are limited by two selective processes, positive selection of T cells bearing receptors that will be useful to the host, and clonal elimination or inactivation of T cells bearing receptors that will be damaging to the host. The ways in which these two apparently contradictory processes occur, and the hypotheses that have been suggested to reconcile them, are discussed.