Receptor

About: Receptor is a research topic. Over the lifetime, 159318 publications have been published within this topic receiving 8299881 citations.

Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin

Abstract: The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite--sphingosine-1-phosphate (S1P)--independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.

Cell surface receptors for extracellular matrix molecules

Abstract: Table 2 lists most of the extracellular matrix and related receptors identified to date. The wide range of binding affinities of these receptors for their ligands may be important to their function. The affinity of integrins for fibronectin is moderate, with a dissociation constant in the micromolar range. This affinity level leads to relatively rapid dissociation and reformation of receptor-ligand complexes. Thus changes in component concentration can shift binding equilibria within minutes (the time scale of many biologic phenomena) and change the number or organization of adhesive complexes. This type of interaction would be useful in motile cells, in which adhesions must form and dissociate rapidly. In contrast, the affinity of the 68-kDa laminin receptor for its ligand is three orders of magnitude higher. Such levels of affinity would be useful in stabilizing tissue. Members of the integrin family appear to recognize an RGD sequence on the ligands to which they bind. Since there are many ligands containing the RGD sequence, the question of specificity arises. Avian integrin shows little specificity and appears to behave as a multifunctional, promiscuous receptor for extracellular matrix molecules. Figure 1 summarizes our current view of the structural and functional features of avian integrin. In contrast, the mammalian receptors for vitronectin and fibronectin are specific for their respective ligands. More than one of these receptors may be present simultaneously on a cell surface, e.g. fibroblasts express receptors for fibronectin, laminin, and vitronectin at the same time. This multiplicity of receptors provides potential mechanisms for generating the adhesive differences among cells believed to play a prominent role in morphogenesis. Further adhesive differences may stem from the formation of different combinations of various alpha- and beta-subunits expressed in the cell. The mechanism of regulation of adhesive interactions with the extracellular matrix is only beginning to be explored. There are several levels at which this regulation might occur. Integrin appears to be more regionalized in more developed cells that are integral parts of tissue structures. Changes in receptor distribution could alter the relative strength of adhesive interactions. In certain instances, avian integrin disappears, or its concentration is reduced, e.g. during the development of embryonic lung (Chen et al 1986) and erythroid cells (Patel & Lodish 1985). Post-translational modifications provide yet another mechanism for regulating integrin-ligand binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Interleukin-1 receptor antagonist.

Abstract: IL-1ra is the first described naturally occurring receptor antagonist of any cytokine or hormone-like molecule. IL-1ra is a member of the IL-1 family by three criteria: amino acid sequence homology of 26 to 30% to IL-1 beta and 19% to IL-1 alpha; similarities in gene structure; and common gene localization to human chromosome 2q14. Two structural variants of IL-1ra exist: sIL-1ra, a secretory molecule produced by monocytes, macrophages, neutrophils, fibroblasts, and other cells; and icIL-1ra, an intracellular molecule produced by keratinocytes and other epithelial cells, macrophages, and fibroblasts. IL-1ra production by monocytes, macrophages, and neutrophils may be regulated in a differential fashion with IL-1 beta. Human IL-1ra binds to both human IL-1RIs and IL-1RIIs on cell surfaces, although with 100-fold greater avidity to IL-1RIs. IL-1ra may bind preferentially to soluble IL-1RIs and not at all to soluble IL-1RIIs. IL-1ra competitively inhibits binding of both IL-1 alpha and IL-1 beta to cell surface receptors without inducing any discernible intracellular responses. All three forms of IL-1 may bind to IL-1 receptors in a similar fashion but IL-1ra may lack the secondary interactions necessary to trigger cell responses. A 100-fold or greater excess of IL-1ra over IL-1 may be necessary to inhibit biological responses to IL-1 both in vitro and in vivo. The roles of sIL-1ra and icIL-1ra in normal physiology or in host defense mechanisms remain unclear. The administration of IL-1ra blocks the effects of IL-1 in some animal models of septic shock, inflammatory arthritis, graft-versus-host disease, and inflammatory bowel disease. The preliminary results of clinical trials in humans indicate possible efficacy of IL-1ra in sepsis syndrome, rheumatoid arthritis, and GVHD.

Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals

Abstract: Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20hi/CD27lo/CD21lo) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20hi/CD27−/CD21lo) when compared with B cells with a classical memory (CD27+) or naive (CD27−/CD21hi) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.