Showing papers on "Receptor published in 2001"
TL;DR: Evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.
Abstract: Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.
4,686 citations
TL;DR: This work has shown that activation of inflammatory and antimicrobial innate immune responses through recognition of Toll-like receptors expressed on dendritic cells triggers functional maturation of dendrites and leads to initiation of antigen-specific adaptive immune responses.
Abstract: Toll-like receptors have a crucial role in the detection of microbial infection in mammals and insects. In mammals, these receptors have evolved to recognize conserved products unique to microbial metabolism. This specificity allows the Toll proteins to detect the presence of infection and to induce activation of inflammatory and antimicrobial innate immune responses. Recognition of microbial products by Toll-like receptors expressed on dendritic cells triggers functional maturation of dendritic cells and leads to initiation of antigen-specific adaptive immune responses.
4,102 citations
TL;DR: The regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood.
Abstract: The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via Gq proteins to phospholipase C-β. The high-affinity receptor state requires both Mg2+ and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has bee...
2,691 citations
TL;DR: Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work.
Abstract: Cholesterol, fatty acids, fat-soluble vitamins, and other lipids present in our diets are not only nutritionally important but serve as precursors for ligands that bind to receptors in the nucleus. To become biologically active, these lipids must first be absorbed by the intestine and transformed by metabolic enzymes before they are delivered to their sites of action in the body. Ultimately, the lipids must be eliminated to maintain a normal physiological state. The need to coordinate this entire lipid-based metabolic signaling cascade raises important questions regarding the mechanisms that govern these pathways. Specifically, what is the nature of communication between these bioactive lipids and their receptors, binding proteins, transporters, and metabolizing enzymes that links them physiologically and speaks to a higher level of metabolic control? Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work.
2,008 citations
TL;DR: The role of estrogen receptors in physiology and pathology has been investigated in the past decade and it was found that there was not one but two distinct and functional estrogen receptors, now called ERα and ERβ.
Abstract: Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ERα and ERβ. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ERα and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen r...
1,950 citations
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TL;DR: Fc gamma Rs offer a paradigm for the biological significance of balancing activation and inhibitory signaling in the expanding family of activation/inhibitory receptor pairs found in the immune system.
Abstract: Since the description of the first mouse knockout for an IgG Fc receptor seven years ago, considerable progress has been made in defining the in vivo functions of these receptors in diverse biological systems. The role of activating Fc gamma Rs in providing a critical link between ligands and effector cells in type II and type III inflammation is now well established and has led to a fundamental revision of the significance of these receptors in initiating cellular responses in host defense, in determining the efficacy of therapeutic antibodies, and in pathological autoimmune conditions. Considerable progress has been made in the last two years on the in vivo regulation of these responses, through the appreciation of the importance of balancing activation responses with inhibitory signaling. The inhibitory FcR functions in the maintenance of peripheral tolerance, in regulating the threshold of activation responses, and ultimately in terminating IgG mediated effector stimulation. The consequences of deleting the inhibitory arm of this system are thus manifested in both the afferent and efferent immune responses. The hyperresponsive state that results leads to greatly magnified effector responses by cytotoxic antibodies and immune complexes and can culminate in autoimmunity and autoimmune disease when modified by environmental or genetic factors. Fc gamma Rs offer a paradigm for the biological significance of balancing activation and inhibitory signaling in the expanding family of activation/inhibitory receptor pairs found in the immune system.
1,771 citations
TL;DR: The discovery of MHC-specific inhibitory receptors in mouse and in human clarified the molecular basis of this important NK cell function, and some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity.
Abstract: Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3 zeta, Fc epsilon RI gamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR(dull) phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.
1,749 citations
TL;DR: A detailed analysis of the patterns of expression of T1Rs and T2Rs is presented, thus providing a view of the representation of sweet and bitter taste at the periphery.
1,652 citations
TL;DR: Analysis of the multiple processes that modulate EGFR signal transduction has revealed new therapeutic opportunities and elucidated mechanisms contributing to the efficacy of existing anticancer treatments.
1,627 citations
TL;DR: This review focuses on proteins that transduce the signals generated at TNF receptors to nuclear targets such as AP-1 and NF-kappaB, which are likely to be used by other members of the TNF family.
1,619 citations
TL;DR: The characterization of corepressor and coactivator complexes, in concert with the identification of the specific interaction motifs in the receptors, has demonstrated the existence of a general molecular mechanism by which different receptors elicit their transcriptional responses in target genes.
Abstract: The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different “orphan” receptors of unknown ligand. Ligands for some of...
TL;DR: Stimulation of oxytocin secretion after kisspeptin administration to rats confirmed this hypothesis that human GPR54 was highly expressed in placenta, pituitary, pancreas, and spinal cord, suggesting a role in the regulation of endocrine function.
TL;DR: The cloning of this receptor, designated P2Y12, is described and evidence that a patient with a bleeding disorder has a defect in this gene is provided, which should facilitate the development of better antiplatelet agents to treat cardiovascular diseases.
Abstract: Platelets have a crucial role in the maintenance of normal haemostasis, and perturbations of this system can lead to pathological thrombus formation and vascular occlusion, resulting in stroke, myocardial infarction and unstable angina. ADP released from damaged vessels and red blood cells induces platelet aggregation through activation of the integrin GPIIb–IIIa and subsequent binding of fibrinogen. ADP is also secreted from platelets on activation, providing positive feedback that potentiates the actions of many platelet activators1. ADP mediates platelet aggregation through its action on two G-protein-coupled receptor subtypes2,3. The P2Y1 receptor couples to Gq and mobilizes intracellular calcium ions to mediate platelet shape change and aggregation4,5. The second ADP receptor required for aggregation (variously called P2YADP, P2YAC, P2Ycyc or P2TAC) is coupled to the inhibition of adenylyl cyclase through Gi. The molecular identity of the Gi-linked receptor is still elusive, even though it is the target of efficacious antithrombotic agents, such as ticlopidine and clopidogrel6,7,8 and AR-C66096 (ref. 9). Here we describe the cloning of this receptor, designated P2Y12, and provide evidence that a patient with a bleeding disorder10 has a defect in this gene. Cloning of the P2Y12 receptor should facilitate the development of better antiplatelet agents to treat cardiovascular diseases.
TL;DR: This work identifies this unknown receptor on macrophages as dectin-1 (ref. 2), a finding that provides new insights into the innate immune recognition of β-glucans.
Abstract: The carbohydrate polymers known as β-1,3-d-glucans exert potent effects on the immune system — stimulating antitumour and antimicrobial activity, for example — by binding to receptors on macrophages and other white blood cells and activating them. Although β-glucans are known to bind to receptors, such as complement receptor 3 (ref. 1), there is evidence that another β-glucan receptor is present on macrophages. Here we identify this unknown receptor as dectin-1 (ref. 2), a finding that provides new insights into the innate immune recognition of β-glucans.
TL;DR: Rec recombinant EDA, but not other recombinant fibronectin domains, activates human TLR4 expressed in a cell type (HEK 293 cells) that normally lacks this Toll-like receptor.
TL;DR: A novel paradigm of sex steroid action on osteoblasts, osteocytes, embryonic fibroblasts, and HeLa cells involving activation of a Src/Shc/ERK signaling pathway and attenuating apoptosis is demonstrated, providing proof of principle for the development of function-specific-as opposed to tissue-selective-and gender-neutral pharmacotherapeutics.
TL;DR: This minireview will discuss the recent progress toward the understanding of the molecular mechanisms of estrogen signaling, focusing on the following four pathways: 1) classical ligand-dependent; 2) ligand -independent; 3) DNA binding-independent; and 4) cell-surface (nongenomic) signaling.
TL;DR: It is suggested that A2a adenosine receptors are a critical part of the physiological negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses.
Abstract: Inappropriate or prolonged inflammation is the main cause of many diseases; for this reason it is important to understand the physiological mechanisms that terminate inflammation in vivo. Agonists for several Gs-protein-coupled receptors, including cell-surface adenosine purinergic receptors, can increase levels of immunosuppressive cyclic AMP in immune cells; however, it was unknown whether any of these receptors regulates inflammation in vivo. Here we show that A2a adenosine receptors have a non-redundant role in the attenuation of inflammation and tissue damage in vivo. Sub-threshold doses of an inflammatory stimulus that caused minimal tissue damage in wild-type mice were sufficient to induce extensive tissue damage, more prolonged and higher levels of pro-inflammatory cytokines, and death of male animals deficient in the A2a adenosine receptor. Similar observations were made in studies of three different models of inflammation and liver damage as well as during bacterial endotoxin-induced septic shock. We suggest that A2a adenosine receptors are a critical part of the physiological negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses.
TL;DR: These features of RAGE allow the receptor to propagate cellular dysfunction in a number of pathophysiologically relevant situations, most often dictated by the formation and persistence of ligands in the tissues.
Abstract: The multiligand receptors that form the focus of this Perspective series have expectedly diverse functions, often conforming to potential gaps in the host response to invading pathogens that are not effectively manned by adaptive immunity. For example, the macrophage scavenger receptor (type A) interacts with bacterial cell walls and enhances clearance of Gram-negative bacteria from the circulation (1). Similarly, the macrophage mannose receptor binds mannose-rich carbohydrates typical of many microorganisms, thereby promoting their cellular uptake and disposal (2). The present contribution to the series concerns a member of the immunoglobulin superfamily that differs from the above molecules in that all known ligands in its broad repertoire can be generated endogenously (3). This cell surface protein, called RAGE because it serves as a receptor for nonenzymatically glycated adducts termed “advanced glycation endproducts” (AGEs), also binds β-sheet fibrils characteristic of amyloid; proinflammatory cytokine–like mediators of the S100/calgranulin family; and amphoterin, a nuclear protein sometimes found in the ECM (Table (Table11).
Table 1
RAGE ligands and associated pathophysiologic states
Binding of these ligands to RAGE does not accelerate clearance or degradation but rather begins a sustained period of cellular activation mediated by receptor-dependent signaling. This is the first of several distinctive themes that have emerged from studies of RAGE. Other unusual features of the receptor include its ability to engage classes of molecules, rather than individual ligands, and its enhanced surface expression in environments rich in RAGE ligands. This last point is crucial, since it explains how upregulation of this receptor can contribute to an ascending spiral of RAGE-dependent cellular perturbation. Taken together, these features of RAGE allow the receptor to propagate cellular dysfunction in a number of pathophysiologically relevant situations, most often dictated by the formation and persistence of ligands in the tissues. As described below, these diverse situations range from the complications of diabetes and cellular perturbation in amyloidoses to immune and inflammatory responses and tumor cell behavior.
Journal Article•
TL;DR: The role of thrombin in such processes as wound healing and the evidence implicating PAR-1 in vascular disorders and cancer are described and advances in the understanding ofPAR-1-mediated intracellular signaling and receptor desensitization are identified.
Abstract: Proteinase-activated receptors are a recently described, novel family of seven-transmembrane G-protein-coupled receptors. Rather then being stimulated through ligand receptor occupancy, activation is initiated by cleavage of the N terminus of the receptor by a serine protease resulting in the generation of a new tethered ligand that interacts with the receptor within extracellular loop-2. To date, four proteinase-activated receptors (PARs) have been identified, with distinct N-terminal cleavage sites and tethered ligand pharmacology. In addition to the progress in the generation of PAR-1 antagonists, we describe the role of thrombin in such processes as wound healing and the evidence implicating PAR-1 in vascular disorders and cancer. We also identify advances in the understanding of PAR-1-mediated intracellular signaling and receptor desensitization. The cellular functions, signaling events, and desensitization processes involved in PAR-2 activation are also assessed. However, other major aspects of PAR-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of PAR-2. The likely physiological and pathophysiological roles for PAR-2 in skin, intestine, blood vessels, and the peripheral nervous system are considered in the context of PAR-2 activation by multiple serine proteases. The recent discovery of PAR-3 and PAR-4 as additional thrombin-sensitive PARs further highlights the complexity in assessing the effects of thrombin in several different systems, an issue that remains to be fully addressed. These discoveries have also highlighted possible PAR–PAR interactions at both functional and molecular levels. The future identification of other PARs and their modes of activation are an important future direction for this expanding field of study.
TL;DR: Three-dimensional structures of the Trk receptors, in one instance in association with a neurotrophin, have revealed the structural bases underlying specificity in neurotrophIn signaling, where key intermediates are localized to different membrane compartments.
TL;DR: The biology of CD36 can be broadly divided in terms of functions that it mediates with or without TSP-1, but it is probable that it acts in concert with other proteins, such as fatty acid–binding proteins, caveola-associated proteins, integrins, cytoskeletal proteins, and signaling molecules, to effect its diverse functions.
Abstract: CD36, identified more than a quarter of a century ago as a platelet integral membrane glycoprotein (glycoprotein IV), was until recently best known as a receptor for thrombospondin-1 (TSP-1). TSP-1 is found in ECMs and platelet α granules, and it participates in cell attachment, motility, and proliferation, as well as in modulation of protease activity, TGF-β activation, neurite outgrowth, and angiogenesis (1). Initially, this receptor-ligand pair was shown to mediate interactions between platelets and monocytes, tumor cells, and matrix. Since then, CD36 has been implicated in multiple biological processes that define it as a multiligand scavenger receptor (see ref. 2 for review). These ligands appear remarkably diverse: In addition to TSP-1, they include long-chain fatty acids, modified LDL, retinal photoreceptor outer segments, Plasmodium falciparum malaria-parasitized erythrocytes, sickle erythrocytes, anionic phospholipids, apoptotic cells, and collagens I and IV. The biology of CD36 can be broadly divided in terms of functions that it mediates with or without TSP-1, but it is probable that it acts in concert with other proteins, such as fatty acid–binding proteins, caveola-associated proteins, integrins, cytoskeletal proteins, and signaling molecules, to effect its diverse functions.
TL;DR: A regulatory role is identified for PPAR-α andPPAR-γ in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.
Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.
TL;DR: It is suggested that OPN delivers an antiapoptotic “ECM-like” signal via multiple ligand-receptor interactions to cells, both adherent and nonadherent.
Abstract: OPN is a multifunctional cytokine and adhesion protein that contains an integrin-binding RGD sequence and additional sequences that interact with CD44v6/7 or other adhesive receptors. Its expression is increased in response to early proinflammatory cytokines and to mechanical strain in bone. The function of the secreted protein may be altered by extracellular enzymes, including thrombin and kinases. The study of OPN-null mice has revealed roles for OPN in a broad range of homeostatic (bone remodeling, tissue debridement) and pathologic (cellular immunity, wound healing, cancer metastasis) processes. While these processes seem disparate, they are linked by several common themes, including enhanced expression of OPN in response to stress or tissue injury, and stimulation of cell motility and cell survival pathways via interactions of OPN with adhesive receptors.
OPN is chemotactic for various cell types, notably monocytes/macrophages, which are attracted to sites of infection and inflammation. It is essential for cell-mediated immunity and a normal Th1 cytokine response during granuloma formation. OPN serves both to attach bone cells to bone matrix and to generate intracellular signals essential for normal osteoclast motility on bone; it may mediate osteocyte recognition of bone strain. OPN activates intracellular signaling pathways and regulates gene expression as a consequence of its interactions with its various receptors. The best-characterized is the integrin-stimulated FAK-Src-Rho pathway, which alters gelsolin function and podosome formation in osteoclasts. Identification and dissection of the signal transduction pathways and their targets are complicated by the fact that OPN can engage more than one type of receptor on the cell. For this reason, it is important to ascertain which receptors are in play in any given experimental system.
There is compelling evidence that soluble OPN can in a variety of situations help cells survive an otherwise lethal insult. Remarkably, this survival signaling is mediated by receptors that are generally considered to be receptors for ECM components. We suggest that OPN delivers an antiapoptotic “ECM-like” signal via multiple ligand-receptor interactions to cells, both adherent and nonadherent.
TL;DR: It is shown that a seven-transmembrane receptor, CRTH2, which is preferentially expressed in T helper type 2 (Th2) cells, eosinophils, and basophils in humans, serves as the novel receptor for PGD2.
Abstract: Prostaglandin (PG)D2, which has long been implicated in allergic diseases, is currently considered to elicit its biological actions through the DP receptor (DP). Involvement of DP in the formation of allergic asthma was recently demonstrated with DP-deficient mice. However, proinflammatory functions of PGD2 cannot be explained by DP alone. We show here that a seven-transmembrane receptor, CRTH2, which is preferentially expressed in T helper type 2 (Th2) cells, eosinophils, and basophils in humans, serves as the novel receptor for PGD2. In response to PGD2, CRTH2 induces intracellular Ca2+ mobilization and chemotaxis in Th2 cells in a Gαi-dependent manner. In addition, CRTH2, but not DP, mediates PGD2-dependent cell migration of blood eosinophils and basophils. Thus, PGD2 is likely involved in multiple aspects of allergic inflammation through its dual receptor systems, DP and CRTH2.
TL;DR: Vascular endothelial growth factor (VEGF) is a secreted mitogen highly specific for cultured endothelial cells and plays a central role in both angiogenesis and vasculogenesis, most notably the neovascularisation of growing tumours.
Abstract: Vascular endothelial growth factor (VEGF) is a secreted mitogen highly specific for cultured endothelial cells. In vivo VEGF induces microvascular permeability and plays a central role in both angiogenesis and vasculogenesis. VEGF is a promising target for therapeutic intervention in certain pathological conditions that are angiogenesis dependent, most notably the neovascularisation of growing tumours. Through alternative mRNA splicing, a single gene gives rise to several distinct isoforms of VEGF, which differ in their expression patterns as well as their biochemical and biological properties. Two VEGF receptor tyrosine kinases (VEGFRs) have been identified, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 seems to mediate almost all observed endothelial cell responses to VEGF, whereas roles for VEGFR-1 are more elusive. VEGFR-1 might act predominantly as a ligand-binding molecule, sequestering VEGF from VEGFR-2 signalling. Several isoform-specific VEGF receptors exist that modulate VEGF activity. Neuropilin-1 acts as a co-receptor for VEGF(165), enhancing its binding to VEGFR-2 and its bioactivity. Heparan sulphate proteoglycans (HSPGs), as well as binding certain VEGF isoforms, interact with both VEGFR-1 and VEGFR-2. HSPGs have a wide variety of functions, such as the ability to partially restore lost function to damaged VEGF(165) and thereby prolonging its biological activity.
TL;DR: Alternative splice variants described that alter the coding sequence in the C-terminal intracellular tail region modulate signal transduction, phosphorylation, and desensitization of these receptors, as well as altering agonist-independent constitutive activity.
Abstract: Cyclooxygenases metabolize arachidonate to five primary prostanoids: PGE2, PGF2α, PGI2, TxA2, and PGD2. These autacrine lipid mediators interact with specific members of a family of distinct G-protein-coupled prostanoid receptors, designated EP, FP, IP, TP, and DP, respectively. Each of these receptors has been cloned, expressed, and characterized. This family of eight prostanoid receptor complementary DNAs encodes seven transmembrane proteins which are typical of G-protein-coupled receptors and these receptors are distinguished by their ligand-binding profiles and the signal transduction pathways activated on ligand binding. Ligand-binding selectivity of these receptors is determined by both the transmembrane sequences and amino acid residues in the putative extracellular-loop regions. The selectivity of interaction between the receptors and G proteins appears to be mediated at least in part by the C-terminal tail region. Each of the EP1, EP3, FP, and TP receptors has alternative splice variants describe...
TL;DR: BAFF-R appears to be the principal receptor for BAFF-mediated mature B cell survival and is disrupted in A/WySnJ mice, which display a B cell phenotype qualitatively similar to that of the BAff-deficient mice.
Abstract: B cell homeostasis has been shown to critically depend on BAFF, the B cell activation factor from the tumor necrosis factor (TNF) family Although BAFF is already known to bind two receptors, BCMA and TACI, we have identified a third receptor for BAFF that we have termed BAFF-R BAFF-R binding appears to be highly specific for BAFF, suggesting a unique role for this ligand-receptor interaction Consistent with this, the BAFF-R locus is disrupted in A/WySnJ mice, which display a B cell phenotype qualitatively similar to that of the BAFF-deficient mice Thus, BAFF-R appears to be the principal receptor for BAFF-mediated mature B cell survival
TL;DR: The view of the role of estrogen in neural function must be broadened to include not only its function in neuroendocrine regulation and reproductive behaviors, but also to include a direct protective role in response to degenerative disease or injury.
TL;DR: In this paper, the authors analyzed circulating levels of cytokines (tumor necrosis factor [TNF] and interleukin-6) and their cognate receptors in 1200 consecutive patients who were enrolled in a multicenter clinical trial of patients with advanced heart failure.
Abstract: Background—Previous reports have shown that elevated circulating levels of cytokines and/or cytokine receptors predict adverse outcomes in patients with heart failure. However, these studies were limited by small numbers of patients and/or they were performed in a single center. In addition, these studies did not have sufficient size to address the influence of age, race, sex, and cause of heart failure on the circulating levels of these inflammatory mediators in patients with heart failure. Methods and Results—We analyzed circulating levels of cytokines (tumor necrosis factor [TNF] and interleukin-6) and their cognate receptors in 1200 consecutive patients who were enrolled in a multicenter clinical trial of patients with advanced heart failure. This analysis constitutes the largest analysis of cytokines and cytokine receptors to date. Analysis of the patients receiving placebo showed that increasing circulating levels of TNF, interleukin-6, and the soluble TNF receptors were associated with increased mo...