Biphasic Regulation in Ligand-Receptor Interactions

Abstract

A model is examined in which an excess of activator may inhibit the response in a ligand-receptor interaction. The equation accounts for biphasic responses in which an effector stimulates the response at low concentrations and then inhibits the response at higher concentrations, towards a limit that can be higher, identical or lower than the initial value. Reciprocal features could be observed according to the values of the involved parameters. A maximum 7 dimensions can be found in the space of the parameters of the equation which is of the simple form: v = (A + B + C). Sⁿ/(H + Sⁿ).     

纳米形貌诱导干细胞成骨分化的相关信号通路

目的:探究纳米形貌诱导间充质干细胞(MSC)分化中的作用以及相关分子机制。方法:利用阳极氧化法制备二氧化钛纳米管形貌,使用qRT-PCR技术,RNA-seq技术,分析接种在纳米形貌表面的间充质干细胞的基因表达情况。并筛选对成骨相关的信号通路中的成员,观察他们基因上调或下调情况。结果:在钛金属表面构建出了纳米形貌,利用实时定量PCR确定了成骨相关的基因:碱性磷酸酶(ALP),骨桥蛋白(OPN)和骨钙素(OCN)相比没有纳米形貌的钛片上培养的细胞均发生上调。通过对这些基因相关的成骨信号通路进行转录组数据分析(筛选基因P<0.05),发现在BMP2信号通路中的相关蛋白基因表达没有太大变化,同时Notch以及Wnt非经典信号通路中相关蛋白基因发生较为明显变化。结论:通过分析间充质干细胞成骨分化相关基因,以及转录组数据分析表明在纳米形貌诱导BMSC分化过程中,相对于平坦的表面,纳米形貌启动了Notch以及非经典的Wnt信号通路,因此表现出更加优良的促成骨分化的效果。     

Enhancer and competitive allosteric modulation model for G-protein-coupled receptors

A new mathematical model, referred to as Enhancer and Competitive Allosteric Modulator (ECAM) model, developed with the aim of quantitatively describing the interaction of an allosteric modulator with both enhancer and competitive properties towards G-protein-coupled receptors is described here. Model simulations for equilibrium (displacement-like and saturation-like), and kinetic (association and dissociation) binding experiments were performed. The results showed the ability of the model to interpret a number of possible ligand-receptor binding behaviors. In particular, the binding properties of PD81723, an enhancer and competitive allosteric modulator for the adenosine A₁ receptor, were experimentally evaluated by radioligand binding assays and interpreted by the ECAM model. The results also offer a theoretical background enabling the design and optimization of compounds endowed with allosteric enhancer, competitive, agonist, antagonist, and inverse agonist properties.     

Gap junctions: structure and function (Review)

Gap junctions are plasma membrane spatial microdomains constructed of assemblies of channel proteins called connexins in vertebrates and innexins in invertebrates. The channels provide direct intercellular communication pathways allowing rapid exchange of ions and metabolites up to ~1 kD in size. Approximately 20 connexins are identified in the human or mouse genome, and orthologues are increasingly characterized in other vertebrates. Most cell types express multiple connexin isoforms, making likely the construction of a spectrum of heteromeric hemichannels and heterotypic gap junctions that could provide a structural basis for the charge and size selectivity of these intercellular channels. The precise nature of the potential signalling information traversing junctions in physiologically defined situations remains elusive, but extensive progress has been made in elucidating how connexins are assembled into gap junctions. Also, participation of gap junction hemichannels in the propagation of calcium waves via an extracellular purinergic pathway is emerging. Connexin mutations have been identified in a number of genetically inherited channel communication-opathies. These are detected in connexin 32 in Charcot Marie Tooth-X linked disease, in connexins 26 and 30 in deafness and skin diseases, and in connexins 46 and 50 in hereditary cataracts. Biochemical approaches indicate that many of the mutated connexins are mistargeted to gap junctions and/or fail to oligomerize correctly into hemichannels. Genetic ablation approaches are helping to map out a connexin code and point to specific connexins being required for cell growth and differentiation as well as underwriting basic intercellular communication.     

Docking studies suggest ligand-specific δ-opioid receptor conformations

An automated docking procedure was used to study binding of a series of δ-selective ligands to three models of the δ-opioid receptor. These models are thought to represent the three ligand-specific receptor conformations. Docking results are in agreement with point mutation studies and suggest that different ligands—agonists and antagonists—may bind to the same binding site under different receptor conformations. Docking to different receptor models (conformations) also suggests that by changing to a receptor-specific conformation, the receptor may open or close different binding sites to other ligands. Figure  Ligands 5 (green) and 6 (orange) in bindingpocket BP1 of the R1 δ-opioid receptor model     

Integration of omics sciences to advance biology and medicine

In the past two decades, our ability to study cellular and molecular systems has been transformed through the development of omics sciences. While unlimited potential lies within massive omics datasets, the success of omics sciences to further our understanding of human disease and/or translating these findings to clinical utility remains elusive due to a number of factors. A significant limiting factor is the integration of different omics datasets (i.e., integromics) for extraction of biological and clinical insights. To this end, the National Cancer Institute (NCI) and the National Heart, Lung and Blood Institute (NHLBI) organized a joint workshop in June 2012 with the focus on integration issues related to multi-omics technologies that needed to be resolved in order to realize the full utility of integrating omics datasets by providing a glimpse into the disease as an integrated “system”. The overarching goals were to (1) identify challenges and roadblocks in omics integration, and (2) facilitate the full maturation of ‘integromics’ in biology and medicine. Participants reached a consensus on the most significant barriers for integrating omics sciences and provided recommendations on viable approaches to overcome each of these barriers within the areas of technology, bioinformatics and clinical medicine.     

Signaling induced by hop/STI-1 depends on endocytosis

The co-chaperone hop/STI-1 is a ligand of the cell surface prion protein (PrP(C)), and their interaction leads to signaling and biological effects. Among these, hop/STI-1 induces proliferation of A172 glioblastoma cells, dependent on both PrP(C) and activation of the Erk pathway. We tested whether clathrin-mediated endocytosis affects signaling induced by hop/STI-1. Both hyperosmolarity induced by sucrose and monodansyl-cadaverine blocked Erk activity induced by hop/STI-1, without affecting the high basal Akt activity typical of A172. The endocytosis inhibitors also affected the sub-cellular distribution of phosphorylated Erk, consistent with blockade of the latter's activity. The data indicate that signaling induced by hop/STI-1 depends on endocytosis. These findings are consistent with a role of sub-cellular trafficking in signal transduction following engagement by PrP(C) by ligands such as hop/STI-1, and may help help unravel both the functions of the prion protein, as well as possible loss-of-function components of prion diseases.     

Stochastic simulations of nanoparticle internalization through transferrin receptor dependent clathrin-mediated endocytosis

Background

Receptor dependent clathrin-mediated endocytosis (CME) is one of the most important endocytic pathways for the internalization of bioparticles into cells. During CME, the ligand-receptor interactions, development of clathrin-coated pit (CCP) and membrane evolution all act together to drive the internalization of bioparticles. In this work, we develop a stochastic computational model to investigate the CME based on the Metropolis Monte Carlo simulations.

Phytochrome-dependent modulation and re-induction of growth of the first rhizoid in Dryopteris paleacea Sw

Phytochrome-dependent growth in Dryopteris paleacea Sw. was investigated in young, developing gametophytes with respect to formation and differentiation of rhizoids. Under continuous red light (Rc), the first rhizoids grew synchronously by tip elongation at a constant rate of 240 μm · d⁻¹ until formation and outgrowth of the second rhizoid. Cessation of growth of the first rhizoids and outgrowth of the second rhizoids showed a correlation in time assumed to be mediated by intercellular signaling. The first rhizoids showed two modes of response to actinic irradiations: (i) modulation of rhizoid growth, and (ii) re-induction of growth in non-growing rhizoids. In the former, the promotory effect of actinic irradiations on rhizoids pre-cultured under Rc determined both the time for which rhizoids continued to grow after transfer into darkness and the final rhizoid length. In the latter, re-induced growth was studied using non-growing rhizoids which were obtained after irradiation with a far-red light (FR) pulse at the end of the pre-culture in Rc and transfer into darkness for 3 d to stop growth. Re-induction of growth occurred with a lag phase of 36 to 48 h after formation of the FR-absorbing form of phytochrome (Pfr) by a red light (R) pulse. From the incomplete R/FR reversibility it is evident that, here, coupling of Pfr to signal transduction is possible within minutes. Re-induction of growth possesses the advantage that the effect of actinic irradiations can be studied as an all-or-none response at the level of single gametophytes in future experiments. The present results clearly indicate that the developmental stage of the whole gametophyte, i.e. temporal and spatial patterns undergone during development, affects the regulation of rhizoid growth by the external factor light. Received: 8 June 1998 / Accepted: 22 December 1998     

A family of halobacterial transducer proteins

Abstract A DNA probe to the signaling domain of a halobacterial transducer for phototaxis (HtrI) was used to clone and sequence four members of a new family of transducer proteins (Htps) in Halobacterium salinarium potentially involved in chemo- or phototactic signal transduction. The signaling domains in these proteins have 31–43% identity when compared with each other or with their bacterial analogs, the methyl-accepting chemotaxis proteins. An additional region of homology found in three of the Htps has 31–43% identity with Htrl. The Htps contain from 0 to 3 transmembrane helices and Western blotting showed that HtpIII is soluble. The arrangement of the domains in these Htps suggests a modular architecture in their construction.