Showing papers on "Receptor published in 1989"
TL;DR: The isolation of a cloned cDNA encoding a new GABAA receptor subunit, termed γ2, which shares approximately 40% sequence identity with α-and β-subunits and whose messenger RNA is prominently localized in neuronal subpopulations throughout the CNS.
Abstract: NEUROTRANSMISSION effected by GABA (γ-aminobutyric acid) is predominantly mediated by a gated chloride channel intrinsic to the GABAA receptor. This heterooligomeric receptor1 exists in most inhibitory synapses in the vertebrate central nervous system (CNS) and can be regulated by clinically important compounds such as benzodiazepines and barbiturates2. The primary structures of GABAA receptor α- and β-subunits have been deduced from cloned complementary DNAs3,4. Co-expression of these subunits in heterologous systems generates receptors which display much of the pharmacology of their neural counterparts, including potentiation by barbiturates3–5. Conspicuously, however, they lack binding sites for, and consistent electrophysiological responses to, benzodiazepines4,5. We now report the isolation of a cloned cDNA encoding a new GABAA receptor subunit, termed γ2, which shares approximately 40% sequence identity with α-and β-subunits and whose messenger RNA is prominently localized in neuronal subpopulations throughout the CNS. Importantly, coexpression of the γ2 subunit with α1 and β1 subunits produces GABAA receptors displaying high-affinity binding for central benzodiazepine receptor ligands.
1,334 citations
TL;DR: The major human rhinovirus receptor has been identified with monoclonal antibodies that inhibit rhInovirus infection and protein sequence from the 95 kd protein showed an identity with that of intercellular adhesion molecule-1 (ICAM-1).
1,144 citations
TL;DR: The results indicate that stimulation of NMDA receptors results in the activation of the enzyme which catalyzes the formation of NO from L-arginine, a stimulator of soluble guanylate cyclase.
909 citations
TL;DR: Identity between the receptor for the major group of rhinoviruses and ICAM-1 is demonstrated, suggesting that the host immune response to rh inovirus may facilitate spread to uninfected cells.
817 citations
TL;DR: It is shown clearly that cultured T lymphocytes use two independent receptors during attachment to fibronectin and that alpha 5 beta 1 is the receptor for the RGD containing cell adhesion domain, and (b) alpha 4 beta 1 are the receptors for a carboxy-terminalcell adhesion region containing the Heparin II and IIICS domains.
Abstract: Using mAb technology (Wayner, E. A., W. G. Carter, R. Piotrowicz, and T. J. Kunicki. 1988. J. Cell Biol. 107:1881-1891), we have identified a new fibronectin receptor that is identical to the integrin receptor alpha 4 beta 1. mAbs P3E3, P4C2, and P4G9 recognized epitopes on the alpha 4 subunit and completely inhibited the adhesion of peripheral blood and cultured T lymphocytes to a 38-kD tryptic fragment of plasma fibronectin containing the carboxy-terminal Heparin II domain and part of the type III connecting segment (IIICS). The ligand in IIICS for alpha 4 beta 1 was the CS-1 region previously defined as an adhesion site for melanoma cells. The functionally defined mAbs to alpha 4 partially inhibited T lymphocyte adhesion to intact plasma fibronectin and had no effect on their attachment to an 80-kD tryptic fragment containing the RGD (arg-gly-asp) adhesion sequence. mAbs (P1D6 and P1F8) to the previously described fibronectin receptor, alpha 5 beta 1, completely inhibited T lymphocyte adhesion to the 80-kD fragment but had no effect on their attachment to the 38-kD fragment or to CS-1. Both alpha 4 beta 1 and alpha 5 beta 1 localized to focal adhesions when fibroblasts that express these receptors were grown on fibronectin-coated surfaces. These findings demonstrated a specific interaction of both receptors with fibronectin at focal contacts. In conclusion, these findings show clearly that cultured T lymphocytes use two independent receptors during attachment to fibronectin and that (a) alpha 5 beta 1 is the receptor for the RGD containing cell adhesion domain, and (b) alpha 4 beta 1 is the receptor for a carboxy-terminal cell adhesion region containing the Heparin II and IIICS domains. Furthermore, these data also show that T lymphocytes express a clear preference for a region of molecular heterogeneity in IIICS (CS-1) generated by alternative splicing of fibronectin pre-mRNA and that alpha 4 beta 1 is the receptor for this adhesion site.
802 citations
TL;DR: The domain organization of GMP-140 is similar to that of ELAM-1, a cytokine-inducible endothelial cell receptor that binds neutrophils, which suggests that GMp-140 belongs to a new family of inducible receptors with related structure and function on vascular cells.
796 citations
TL;DR: Two independent cDNA clones encoding the erythropoietin receptor (EPO-R) were isolated from a pXM expression library made from uninduced murine erythroleukemia (MEL) cells and showed no similarities to known proteins or nucleic acid sequences in the data bases.
711 citations
TL;DR: An approach based on the polymerase chain reaction has been devised to clone new members of the family of genes encoding guanosine triphosphate-binding protein (G protein)-coupled receptors, suggesting that they are members of a new subfamily of receptors with a very short nonglycosylated amino-terminal extension.
Abstract: An approach based on the polymerase chain reaction has been devised to clone new members of the family of genes encoding guanosine triphosphate-binding protein (G protein)-coupled receptors. Degenerate primers corresponding to consensus sequences of the third and sixth transmembrane segments of available receptors were used to selectively amplify and clone members of this gene family from thyroid complementary DNA. Clones encoding three known receptors and four new putative receptors were obtained. Sequence comparisons established that the new genes belong to the G protein-coupled receptor family. Close structural similarity was observed between one of the putative receptors and the 5HT1a receptor. Two other molecules displayed common sequence characteristics, suggesting that they are members of a new subfamily of receptors with a very short nonglycosylated (extracellular) amino-terminal extension.
708 citations
TL;DR: It is shown that the gene for the D2 receptor produces two receptor isoforms by alternative messenger RNA splicing, providing a route to receptor diversity in this family of receptors.
Abstract: Dopamine receptors are classified into D1 and D2 subtypes on the basis of their pharmacological properties and the intracellular responses they mediate. The cerebral D2 dopamine receptor is the target of drugs used to alleviate the main symptoms of schizophrenia. Although it is considered to be a single molecular entity, there is evidence that multiple D2-receptor subtypes exist. A complementary DNA encoding a D2 receptor has recently been cloned and the deduced 415-amino-acid sequence indicates that it belongs to the large superfamily of receptors coupled to G proteins, and that its topology consists of seven transmembrane domains. In this family, the genes are frequently without introns and each is believed to encode a unique polypeptide product. Here we show that the gene for the D2 receptor produces two receptor isoforms by alternative messenger RNA splicing, providing a route to receptor diversity in this family. One isoform corresponds to the D2(415) receptor, but the second contains an additional sequence encoding a 29-amino-acid fragment, defining a novel D2(444) receptor isoform. Expression of the two isoforms is tissue-specific, and both are regulated by guanyl nucleotides. As the extra sequence is located within a putative cytoplasmic loop that binds to G proteins, the two isoforms might interact with different G proteins and thereby initiate distinct intracellular signals.
705 citations
Journal Article•
TL;DR: The properties and uses of a monoclonal antibody, H57-597, produced from hamsters, which reacts with surface receptors on all alpha beta TCR-bearing cells and does not react with receptors on gamma delta+ T cells.
Abstract: Research on the specificities, functions, and maturation of T cells would be greatly aided by a collection of monoclonal antibodies which distinguishes different types of TCR. With this end in mind hamsters were immunized and tested for production of pan-reactive anti-mouse alpha beta TCR antibodies. In this report we describe the properties and uses of a mAb, H57-597, produced from one of these animals. The mAb reacts with surface receptors on all alpha beta TCR-bearing cells and does not react with receptors on gamma delta+ T cells. In an immobilized form, this antibody can directly activate T cells bearing alpha beta TCR. It can be used in immunoprecipitation reactions to precipitate receptor from the appropriate cell types. In combination with anti-CD3, the antibody can be used in cytofluorographic analyses to measure numbers of CD3+, alpha beta+, and CD3+, gamma delta+ cells in the thymus and periphery.
TL;DR: Results indicate that cyclosporin A either directly inhibits the function of nuclear proteins critical to T lymphocyte activation or inhibits the action of a more proximal member of the signal transmission cascade leading from the antigen receptor to the nucleus.
Abstract: One action of cyclosporin A thought to be central to many of its immunosuppressive effects is its ability to inhibit the early events of T lymphocyte activation such as lymphokine gene transcription in response to signals initiated at the antigen receptor. Cyclosporin A was found to specifically inhibit the appearance of DNA binding activity of NF-AT, AP-3, and to a lesser extent NF-kappa B, nuclear proteins that appear to be important in the transcriptional activation of the genes for interleukin-2 and its receptor, as well as several other lymphokines. In addition, cyclosporin A abolished the ability of the NF-AT binding site to activate a linked promoter in transfected mitogen-stimulated T lymphocytes and in lymphocytes from transgenic mice. These results indicate that cyclosporin A either directly inhibits the function of nuclear proteins critical to T lymphocyte activation or inhibits the action of a more proximal member of the signal transmission cascade leading from the antigen receptor to the nucleus.
TL;DR: The first recordings of currents through single ion channels activated by 5-HT3 receptors are reported, in excised membrane patches from neurons of the guinea pig submucous plexus, implying a role for 5- HT, and perhaps other amines, as a 'fast' synaptic transmitter.
Abstract: The neurohormone 5-hydroxytryptamine (5HT or serotonin) exerts its effects by binding to several distinct receptors. One of these is the M-receptor of Gaddum and Picarelli, now called the 5-HT3 receptor, through which 5-HT acts to excite enteric neurons. Ligand-binding and functional studies have shown that the 5-HT3 receptor is widely distributed in peripheral and central nervous tissue and evidence suggests that the receptor might incorporate an ion channel permeable to cations. We now report the first recordings of currents through single ion channels activated by 5-HT3 receptors, in excised (outside-out) membrane patches from neurons of the guinea pig submucous plexus. Whereas application of acetylcholine activated predominantly a 40-pS channel, 5-HT caused unitary currents apparently through two channels of conductances of 15 and 9 pS, which were reversibly blocked by antagonists of the 5-HT3 receptor. Receptors for amine neurotransmitters, including 5-HT1 and 5-HT2, have previously been thought to transduce their effects through GTP-binding proteins: the direct demonstration that 5-HT3 receptors are ligand-gated ion channels implies a role for 5-HT, and perhaps other amines, as a 'fast' synaptic transmitter.
Journal Article•
TL;DR: The diverse binding profiles of individual cloned receptors and the widespread distribution of m1-m4 mRNAs indicate that radioligand binding studies performed on primary tissues may actually be assessing the composite properties of a heterogeneous mixture of muscarinic receptor subtypes.
Abstract: A family of five cholinergic muscarinic receptor genes (m1, m2, m3, m4, and m5) has recently been identified and cloned. In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. m1, m2, and m3 receptors express binding properties similar to those expected of high affinity pirenzepine-type receptors of cerebral cortex ("M1"), low affinity pirenzepine-type receptors of atria ("M2 cardiac type"), and the intermediate affinity pirenzepine-type receptors found in exocrine glands ("M2 glandular type"), respectively. The M1/M2 schema cannot readily accommodate the binding properties of the m4 and m5 receptors. Pirenzepine, methoctramine, and hexahydrosiladifenidol were the most selective agents for the m1, m2, and m3 receptors, respectively. None of the antagonists used in this study were uniquely selective for either the m4 or m5 receptors. The diverse binding profiles of individual cloned receptors and the widespread distribution of m1-m4 mRNAs indicate that radioligand binding studies performed on primary tissues may actually be assessing the composite properties of a heterogeneous mixture of muscarinic receptor subtypes.
TL;DR: The soluble form of the IL-4 receptor blocked the ability ofIL-4 to induce CTLL cell proliferation and may represent a regulatory molecule specific for IL- 4-dependent immune responses.
TL;DR: Evidence is presented that high affinity binding of PDGF requires association of two different receptor subunits: an alpha-subunit that can bind either a B- or an A-chain ofPDGF, and a beta-sub unit that can binds only a B/A-chain.
TL;DR: The sequence of a cDNA clone encoding Bp50 was analyzed and an extensive homology with the nerve growth factor receptor was found, suggesting a role for the molecule in the development of carcinomas at sites of chronic inflammation.
Abstract: B cells and primary carcinomas express a surface molecule, Bp50 (CDw40), absent from other hematopoietic cells and from normal epithelium, and thought to play a regulatory role in B-cell maturation and epithelial neoplasia In this work the sequence of a cDNA clone encoding Bp50 was analyzed by a newly derived transition matrix method Among several interesting relationships with known receptors was found an extensive homology with the nerve growth factor receptor The mRNA is induced by gamma-interferon in both B cells and epithelial neoplasms, suggesting a role for the molecule in the development of carcinomas at sites of chronic inflammation
TL;DR: The identification and cloning of a cDNA encoding an RNA splice variant of the rat D2 receptor cDNA is reported, which codes for a receptor isoform which is predominantly expressed in the brain, and contains an additional 29 amino acids in the third cytoplasmic loop, a region believed to be involved in G protein coupling.
Abstract: DOPAMINE receptors belong to a large class of neurotransmitter and hormone receptors that are linked to their signal transduction pathways through guanine nucleotide binding regulatory proteins (G proteins). Pharmacological, biochemical and physiological criteria have been used to define two subcategories of dopamine receptors1 referred to as D1 and D2. D1 receptors activate adenylyl cyclase2 and are coupled with the Gs regulatory protein3. By contrast, activation of D2 receptors results in various responses including inhibition of adenylyl cyclase4, inhibition of phosphatidylinositol turnover5, increase in K+ channel activity6 and inhibition of Ca2+ mobilization7. The G protein(s) linking the D2 receptors to these responses have not been identified, although D2 receptors have been shown to both copurify8,9 and functionally reconstitute10,11 with both Gi and Go related proteins3. The diversity of responses elicited by D2-receptor activation could reflect the existence of multiple D2 receptor subtypes, the identification of which is facilitated by the recent cloning of a complementary DNA encoding a rat D2 receptor12. This receptor exhibits considerable amino-acid homology with other members of the G protein-coupled receptor superfamily12,13. Here we report the identification and cloning of a cDNA encoding an RNA splice variant of the rat D2 receptor cDNA12. This cDNA codes for a receptor isoform which is predominantly expressed in the brain, and contains an additional 29 amino acids in the third cytoplasmic loop, a region believed to be involved in G protein coupling.
TL;DR: Recent studies of the PDGF receptor have provided insight into how the receptor for PDGF recognize and bind its specific ligand and then transduce this signal across the cell membrane via a single membrane-spanning region.
Abstract: When platelet-derived growth factor (PDGF) binds to its receptor on a quiescent fibroblast or smooth muscle cell, it stimulates a remarkably diverse group of biochemical responses, including changes in ion fluxes, activation of several kinases, alterations in cell shape, increased transcription of a number of genes, and stimulation of enzymes that regulate phospholipid metabolism. These and other reactions culminate, hours later, in DNA replication and cell division. How does the receptor for PDGF recognize and bind its specific ligand and then transduce this signal across the cell membrane via a single membrane-spanning region? Which of the immediate cellular responses are directly involved in the biochemical pathways that lead to DNA synthesis? How does the PDGF receptor trigger a diverse group of responses? Recent studies of the PDGF receptor have provided insight into these issues.
TL;DR: Characterization of the growth hormone receptor gene from nine patients with Laron-type dwarfism shows that two individuals have a deletion of a large portion of the extracellular, hormone binding domain of the receptor gene.
Abstract: Laron-type dwarfism is an autosomal recessive genetic disorder that is characterized by high levels of growth hormone and low levels of insulin-like growth factor I in the circulation. Several lines of evidence suggest that this disease is caused by a defect in the growth hormone receptor. In order to analyze the receptor gene in patients with Laron-type dwarfism and with other growth disorders, we have first determined the gene structure in normal individuals. There are nine exons that encode the receptor and several additional exons in the 5' untranslated region. The coding exons span at least 87 kilobase pairs of chromosome 5. Characterization of the growth hormone receptor gene from nine patients with Laron-type dwarfism shows that two individuals have a deletion of a large portion of the extracellular, hormone binding domain of the receptor gene. Interestingly, this deletion includes nonconsecutive exons, suggesting that an unusual rearrangement may have occurred. Thus, we provide direct evidence that Laron-type dwarfism can result from a defect in the structural gene for the growth hormone receptor.
TL;DR: Results indicate that post-translational modification by palmitate of beta 2AR may play a crucial role in the normal coupling of the receptor to the adenylyl cyclase signal transduction system.
TL;DR: Two nearly identical, linked genes that encode these transcripts have been cloned for Fc gamma RIII(CD16), one of which (III-1) is allelic for NA- 1 and NA-2, and the allelic sites have been mapped to two single nucleotides in the extracellular domain.
Abstract: A low affinity receptor for IgG immune complexes, Fc gamma RIII(CD16), is expressed on human NK cells as an integral membrane glycoprotein anchored through a transmembrane peptide; on polymorphonuclear neutrophils (PMN) the receptor is anchored through a phosphatidylinositol (PI) linkage. The protein on NK cells has a molecular mass 6-10 kD larger than that on PMN, and, unlike the latter, is resistant to PI-specific phospholipase C (PI-PLC). Fc gamma RIII(CD16) transcripts isolated from PMN and NK cells of single donors revealed multiple single nucleotide differences, one of which converts an in frame UGA termination codon to a CGA codon. The resulting open reading frame encodes a longer cytoplasmic domain for Fc gamma RIII(CD16) in NK cells, contributing to its transmembrane anchor. Two nearly identical, linked genes that encode these transcripts have been cloned for Fc gamma RIII(CD16), one of which (III-1) is allelic for NA-1 and NA-2. The allelic sites have been mapped to two single nucleotides in the extracellular domain. These genes are transcribed in a cell type-specific fashion to generate the alternatively anchored forms of this receptor.
TL;DR: Homology analysis revealed an unexpected relationship between ADF and dithiol‐reducing enzyme, thioredoxin, involved in many important biological reactions such as the conversion of ribon nucleotides into deoxyribonucleotides, or the stabilization of glucocorticoid receptors.
Abstract: HTLV-I transformed T cells not only express a large number of interleukin-2 receptors [IL-2R/p55(Tac)], but also produce a factor named ATL-derived factor (ADF) that augments the expression of IL-2R/p55(Tac). Based on a partial N-terminal amino acid sequence, complementary DNA (cDNA) clones for human and mouse ADF were isolated and sequenced. Recombinant ADF produced by COS-7 monkey kidney cells showed IL-2R/Tac inducing activity on YT cells, which are sensitive for ADF. ADF mRNA was strongly expressed in HTLV-I(+) T cells lines, but not in inactivated cells (THP-1, unstimulated PBMC). Furthermore, in normal human peripheral blood mononuclear cells, the expression of ADF mRNA was enhanced by mitogens or phorbol myristate acetate, suggesting a possible involvement of ADF in the lymphocyte activation. Homology analysis revealed an unexpected relationship between ADF and dithiol-reducing enzyme, thioredoxin, involved in many important biological reactions such as the conversion of ribonucleotides into deoxyribonucleotides, or the stabilization of glucocorticoid receptors. The biological significance of the generation of a redox potential in lymphocyte activation, and the possible involvement of dithiol reduction in the induction of IL-2R/Tac are discussed.
TL;DR: The evolutionary and functional implications of this broad, mosaic receptor relationship are discussed, with particular reference to possible structural resemblances between the cognate growth factors.
TL;DR: Altered in the spectrum of integrins, including two fibronectin receptors, on oncogenic transformation of rodent cells are reported, providing explanations for earlier results concerning the interactions of extracellular matrix proteins with the surfaces of tumor cells and offering leads to further understanding of the altered adhesive and migratory behavior of malignant cells.
TL;DR: Stimulation of transcription of reporter genes by the progesterone receptor was inhibited in transfected HeLa cells by co-expressing the estrogen receptor (ER) in an ER-dose- and estrogen-dependent manner, and it is proposed that these observations reflect competition for a functionally limiting transcription factor(s).
TL;DR: It is shown that for a member of this family of receptors (delta opioid receptors in membranes of NG108-15 neuroblastoma-glioma cells), two types of competitive antagonists can be distinguished and one has no intrinsic activity and the second can inhibit GTPase and thus exhibits negative intrinsic activity.
Abstract: According to classical models of drug-receptor interactions, competitive antagonists share with agonists the ability to bind to a common site on the receptor molecule. However, they are different from agonists, as they cannot trigger the "stimulus" that leads to biological responses--i.e., they lack intrinsic activity. For those receptors whose signals are transduced to effector systems by GTP-binding regulatory proteins (G proteins), a mechanistic equivalent of such a stimulus is an increased ability of agonist-bound receptor to accelerate nucleotide exchange and thus GTPase activity on the G-protein molecule. Here we show that for a member of this family of receptors (delta opioid receptors in membranes of NG108-15 neuroblastoma-glioma cells), two types of competitive antagonists can be distinguished. One type has no intrinsic activity, since it neither stimulates nor inhibits the GTPase activity of G proteins and its apparent affinity for the receptor is not altered by pertussis toxin-mediated uncoupling of receptor and G protein. The second type, however, can inhibit GTPase and thus exhibits negative intrinsic activity; its affinity for receptors is increased following uncoupling from G proteins. The existence of antagonists with negative intrinsic activity may be a general feature of several classes of neurotransmitters or hormone receptors and calls for a reevaluation of biological effects produced by competitive antagonists.
TL;DR: Cl cloning of a murine cDNA that encodes the antigen recognized by the MEL-14 antibody shows that it contains a lectin domain that appears to be involved in the binding of lymphocytes to peripheral lymph node endothelium, thus defining a new type of cellular adhesion molecule.
TL;DR: The cloning of cDNAs and genes for five different muscarinic acetylcholine receptors provides a new basis for characterizingMuscarinic receptor function and it appears likely that much of the difference between functionally similar receptors will be found to lie in their regulation.
TL;DR: The isolation of CD4- CD8-, γ/δ TCR bearing T cell clones from the synovial fluid of a rheumatoid arthritis patient respond specifically to mycobacterial antigens without MHC restriction.
Abstract: THE majority of peripheral T cells express a heterodimeric, α/β T-cell receptor, which recognizes specific antigenic peptides bound to self major histocompatibility complex (MHC) molecules, and either the CD4 or CD8 surface markers. An additional subset of T cells1,2, whose physiological function is unknown, express a distinct CD3-associated receptor composed of γ and δ chains1. This subset includes cells lacking both CD4 and CD8 surface markers, which may be involved in autoimmunity3–6. The recognition specificity of the γ/δ receptor is not well characterized and has been defined in only one case to date, a murine cell line which shows MHC-linked specificity7. In this report, we describe the isolation of CD4- CD8-, γ/δ TCR bearing T cell clones from the synovial fluid of a rheumatoid arthritis patient. These T cell clones respond specifically to mycobacterial antigens without MHC restriction.