Connexin-dependent inter-cellular communication increases invasion and dissemination of Shigella in epithelial cells

Shigella flexneri, the causative agent of bacillar dystentery, invades the colonic mucosa where it elicits an intense inflammatory reaction responsible for destruction of the epithelium. During cell invasion, contact with host cells activates the type-III secretion of the Shigella IpaB and IpaC proteins. IpaB and IpaC are inserted into host cell plasma membranes and trigger initial signals that result in actin polymerization, while allowing cytosolic access of other bacterial effectors that further reorganize the cytoskeleton. After internalization, Shigella moves intracellularly and forms protrusions that infect neighbouring cells, promoting bacterial dissemination across the epithelium. Here, we show that during cell invasion, Shigella induces transient peaks in intracellular calcium concentration that are dependent on a functional type-III secretory apparatus. In addition, Shigella invasion induces the opening of Connexin 26 (Cx26) hemichannels in an actin- and phospholipase-C-dependent manner, allowing release of ATP into the medium. The released ATP, in turn, increases bacterial invasion and spreading, as well as calcium signalling induced by Shigella. These results provide evidence that pathogen-induced opening of connexin channels promotes signalling events that favour bacterial invasion and dissemination.     

Melanin-concentrating hormone signaling systems in fish

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide synthesized as a preprohormone in the hypothalamus of all vertebrates. This neuropeptide binds to G-protein-coupled seven transmembrane receptor(s) to mediate its function. MCH was named after its function in teleosts, in which it causes aggregation or concentration of melanin granules in melanophores, thus regulating body color. The function of central MCH that has attracted most attention is its involvement in regulating food intake and energy homeostasis in mammals, a role confirmed through a series of experiments, including central administration of MCH or MCH receptor blockers, and genetic manipulation of MCH and its receptors. The aim of this article is to review the recent data on MCH and MCH receptor signaling systems in fish.     

Dose-response aligned circuits in signaling systems

Cells use biological signal transduction pathways to respond to environmental stimuli and the behavior of many cell types depends on precise sensing and transmission of external information. A notable property of signal transduction that was characterized in the Saccharomyces cerevisiae yeast cell and many mammalian cells is the alignment of dose-response curves. It was found that the dose response of the receptor matches closely the dose responses of the downstream. This dose-response alignment (DoRA) renders equal sensitivities and concordant responses in different parts of signaling system and guarantees a faithful information transmission. The experimental observations raise interesting questions about the nature of the information transmission through DoRA signaling networks and design principles of signaling systems with this function. Here, we performed an exhaustive computational analysis on network architectures that underlie the DoRA function in simple regulatory networks composed of two and three enzymes. The minimal circuits capable of DoRA were examined with Michaelis-Menten kinetics. Several motifs that are essential for the dynamical function of DoRA were identified. Systematic analysis of the topology space of robust DoRA circuits revealed that, rather than fine-tuning the network's parameters, the function is primarily realized by enzymatic regulations on the controlled node that are constrained in limiting regions of saturation or linearity.     

Protein-based signaling systems in tissue engineering

Tissue engineering aims to replace damaged tissues or organs using either transplanted cells or host cells recruited to the target site. Protein signaling is crucial to regulate cell phenotype and thus engineered tissue structure and function. Biomaterial vehicles are being designed to incorporate and locally deliver various molecules involved in this signaling, including both growth factors and peptides that mimick whole proteins. Controlling the concentration, local duration and spatial distribution of these factors is key to their utility and efficacy. Recent advances have been made in the development of polymeric delivery systems intended to achieve this control.     

Microbial signaling and systems biology

A report of the symposium on Signaling and Systems Biology held during the Society for General Microbiology Spring Meeting, 29-30 March 2010, Edinburgh, UK.     

Peptidergic signaling brain systems in diabetes mellitus

One of the key causes of development of diabetes mellitus (DM) and its complications is change in the functional activity of hormonal signaling systems regulated by hormones of different natures, as is shown by literature data and by the results of our study on animal models of DM and on human DM of types 1 and 2. The brain peptidergic systems regulated by melanocortin receptor agonists, neuropeptide Y, glucagon-like peptide-1, kisspeptines, and somatostatin, play an important role in etiology and pathogenesis of DM. However, the data on interrelations between the functional state of these systems and the development of DM and its complications are scarce and contradictory. The changes in the peptidergic systems are usually the result of metabolic and functional disregulations caused by DM but in some cases may themselves become the cause of DM, as is shown in the case of the melanocortin signaling system. This review is focused on functioning of the brain peptidergic systems in DM and on the possible role of changes of their activity in development of the disease. The hypothesis of central genesis of type 2 DM, which based on data on the generation of insulin resistance and disturbances of carbohydrate and lipid metabolism in response to changes of functional activity of the brain signaling systems regulated by neuropeptides, is discussed.     

Model systems for environmental signaling

Studies of environmental signaling in animals have focused primarilyon organisms with relatively constrained responses, both temporallyand phenotypically. In this regard, existing model animals (e.g.,"worms and flies") are particularly extreme. Such animals haverelatively little capacity to alter their morphology in responseto environmental signals. Hence, they exhibit little phenotypicplasticity. On the other hand, basal metazoans exhibit relativelyunconstrained responses to environmental signals and may thusprovide more general insight, insofar as these constraints arelikely traits derived during animal evolution. Such enhancedphenotypic plasticity may result from greater sensitivity toenvironmental signals, or greater abundance of suitable targetcells, or both. Examination of what is known of the componentsof environmental signaling pathways in cnidarians reveals manysimilarities to well-studied model animals. In addition to theseelements, however, macroscopic basal metazoans (e.g., spongesand cnidarians) typically exhibit a system-level capabilityfor integrating environmental information. In cnidarians, thegastrovascular system acts in this fashion, generating localpatterns of signaling (e.g., pressure, shear, and reactive oxygenspecies) via its organism-wide functioning. Contractile regionsof tissue containing concentrations of mitochondrion-rich, epitheliomuscularcells may be particularly important in this regard, servingin both a functional and a signaling context. While the evolutionof animal circulatory systems is usually considered in termsof alleviating surface-to-volume constraints, such systems alsohave the advantage of enhancing the capacity of larger organismsto respond quickly and efficiently to environmental signals.More general features of animals that correlate with relativelyunconstrained responses to environmental signals (e.g., activestem cells at all stages of the life cycle) are also enumeratedand discussed.     

Novel oligodendrocyte transmembrane signaling systems

Antibodies are increasingly being used as tools to study the function of cell surface markers. Several types of responses may occur upon the selective binding of an antibody to an epitope on a receptor. Antibody binding may trigger signals that are normally transduced by endogenous ligands. Moreover, antibody binding may activate normal signals in a manner that disrupts a sequence of events that coordinates either differentiation, mitogenesis, or morphogenesis. Alternately, it is possible that binding elicits either a modified signal or no signal. This article focuses on the cascade of events that occur following specific antibody binding to myelin markers expressed by cultured murine oligodendrocytes. Binding of specific antibodies to the oligodendrocyte membrane surface markers myelin/oligodendrocyte glycoprotein (MOG), myelin/oligodendrocyte specific protein (MOSP), galactocerebroside (GalC), and sulfatide on cultured murine oligodendrocytes results in different effects with regard to phospholipid turnover, Ca²⁺ influxes, and antibody:marker distribution. The consequence of each antibody-elicited cascade of events appears to be the regulation of the cytoskeleton within the oligodendroglial membrane sheets. The antibody binding studies described in this article demonstrate that these myelin surface markers are capable of transducing signals. Since endogenous ligands for these myelin markers have yet to be identified, it is not known if these signals are normally transduced or are a modification of normally transduced signals.     

Comparative study of neuropeptide signaling systems in Hemiptera

Numerous physiological processes in insects are tightly regulated by neuropeptides and their receptors. Although they form an ancient signaling system, there is still a great deal of variety in neuropeptides and their receptors among different species within the same order. Neuropeptides and their receptors have been documented in many hemipteran insects, but the differences among them have been poorly characterized. Commercial grapevines worldwide are plagued by the bug Daktulosphaira vitifoliae (Hemiptera: Sternorrhyncha). Here, 33 neuropeptide precursors and 48 putative neuropeptide G protein-coupled receptor (GPCR) genes were identified in D. vitifoliae. Their expression profiles at the probe and feeding stages reflected potential regulatory roles in probe behavior. By comparison, we found that the Releasing Hormone-Related Peptides (GnRHs) system of Sternorrhyncha was differentiated from those of the other 2 suborders in Hemiptera. Independent secondary losses of the adipokinetic hormone/corazonin-related peptide receptor (ACP) and corazonin (CRZ) occurred during the evolution of Sternorrhyncha. Additionally, we discovered that the neuropeptide signaling systems of Sternorrhyncha were very different from those of Heteroptera and Auchenorrhyncha, which was consistent with Sternorrhyncha's phylogenetic position at the base of the order. This research provides more knowledge on neuropeptide systems and sets the groundwork for the creation of novel D. vitifoliae management strategies that specifically target these signaling pathways.     

Neuronal signaling systems and ethanol dependence

In recent years there have been remarkable developments toward the understanding of the molecular and/or cellular changes in the neuronal second-messenger pathways during ethanol dependence. In general, it is believed that the cyclic adenosine 3′, 5′-monophosphate (cAMP) and the phosphoinositide (PI) signal-transduction pathways may be the intracellular targets that mediate the action of ethanol and ultimately contribute to the molecular events involved in the development of ethanol tolerance and dependence. Several laboratories have demonstrated that acute ethanol exposure increases, whereas protracted ethanol exposure decreases, agonist-stimulated adenylate cyclase activity in a variety of cell systems, including the rodent brain. Recent studies indicate that various postreceptor events of the cAMP signal transduction cascade (i.e., G_s protein, protein kinase A [PKA], and cAMP-responsive element binding protein [CREB]) in the rodent brain are also modulated by chronic ethanol exposure. The PI signal-transduction cascade represents another important second-messenger system that is modulated by both acute and chronic ethanol exposure in a variety of cell systems. It has been shown that protracted ethanol exposure significantly decreases phospholipase C (PLC) activity in the cerebral cortex of mice and rats. The decreased PLC activity during chronic ethanol exposure may be caused by a decrease in the protein levels of the PLC-Β₁ isozyme but not of PLC-δ₁ or PLC-γ₁ isozymes in the rat cerebral cortex. Protein kinase C (PKC), which is a key step in the Pi-signaling cascade, has been shown to be altered in a variety of cell systems by acute or chronic ethanol exposure. It appears from the literature that PKC plays an important role in the modulation of the function of various neurotransmitter receptors (e.g., γ-aminobutyrate type A [GABAa], N-methyl-D-aspartate [NMDA], serotonin2A [5-HT2a], and 5-HT2C, and muscarinic [m1] receptors) resulting from ethanol exposure. The findings described in this review article indicate that neuronal-signaling proteins represent a molecular locus for the action of ethanol and are possibly involved in the neuroadaptational mechanisms to protracted ethanol exposure. These findings support the notion that alterations in the cAMP and the PI-signaling cascades during chronic ethanol exposure could be the critical molecular events associated with the development of ethanol dependence.     

The systems biology of signaling pathways

Signaling networks play the central role in the regulation of processes in a single cell and in the entire body. A recent breakthrough in technologies for systems biology, which combine experimental and mathematical methods, permits scientists to model signaling pathways in an individual cell and in cell populations. This approach provides new information on mechanisms that regulate a variety of biological processes. Here we discuss the mathematical formalisms that are applied to signaling pathway modeling and relevant experimental methods.     

Optically inducible membrane recruitment and signaling systems

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