Octopamine underlies the counter-regulatory response to a glucose deficit in honeybees (Apis mellifera)

An animal’s internal state is a critical parameter required for adaptation to a given environment. An important aspect of an animal’s internal state is the energy state that is adjusted to the needs of an animal by energy homeostasis. Glucose is one essential source of energy, especially for the brain. A shortage of glucose therefore triggers a complex response to restore the animal’s glucose supply. This counter-regulatory response to a glucose deficit includes metabolic responses like the mobilization of glucose from internal glucose stores and behavioral responses like increased foraging and a rapid intake of food. In mammals, the catecholamines adrenalin and noradrenalin take part in mediating these counter-regulatory responses to a glucose deficit. One candidate molecule that might play a role in these processes in insects is octopamine (OA). It is an invertebrate biogenic amine and has been suggested to derive from an ancestral pathway shared with adrenalin and noradrenalin. Thus, it could be hypothesized that OA plays a role in the insect’s counter- regulatory response to a glucose deficit. Here we tested this hypothesis in the honeybee (Apis mellifera), an insect that, as an adult, mainly feeds on carbohydrates and uses these as its main source of energy. We investigated alterations of the hemolymph glucose concentration, survival, and feeding behavior after starvation and examined the impact of OA on these processes in pharmacological experiments. We demonstrate an involvement of OA in these three processes in honeybees and conclude there is an involvement of OA in regulating a bee’s metabolic, physiological, and behavioral response following a phase of prolonged glucose deficit. Thus, OA in honeybees acts similarly to adrenalin and noradrenalin in mammals in regulating an animal’s counter- regulatory response

Regulation of MCP-1 chemokine transcription by p53

<p>Abstract</p> <p>Background</p> <p>Our previous studies showed that the expression of the monocyte-chemoattractant protein (MCP)-1, a chemokine, which triggers the infiltration and activation of cells of the monocyte-macrophage lineage, is abrogated in human papillomavirus (HPV)-positive premalignant and malignant cells. <it>In silico </it>analysis of the MCP-1 upstream region proposed a putative p53 binding side about 2.5 kb upstream of the transcriptional start. The aim of this study is to monitor a physiological role of p53 in this process.</p> <p>Results</p> <p>The proposed p53 binding side could be confirmed <it>in vitro </it>by electrophoretic-mobility-shift assays and <it>in vivo </it>by chromatin immunoprecipitation. Moreover, the availability of p53 is apparently important for chemokine regulation, since TNF-α can induce MCP-1 only in human keratinocytes expressing the viral oncoprotein E7, but not in HPV16 E6 positive cells, where p53 becomes degraded. A general physiological role of p53 in MCP-1 regulation was further substantiated in HPV-negative cells harboring a temperature-sensitive mutant of p53 and in Li-Fraumeni cells, carrying a germ-line mutation of p53. In both cases, non-functional p53 leads to diminished MCP-1 transcription upon TNF-α treatment. In addition, siRNA directed against p53 decreased MCP-1 transcription after TNF-α addition, directly confirming a crosstalk between p53 and MCP-1.</p> <p>Conclusion</p> <p>These data support the concept that p53 inactivation during carcinogenesis also affects immune surveillance by interfering with chemokine expression and in turn communication with cells of the immunological compartment.</p

The systematic annotation of the three main GPCR families in Reactome

Reactome is an open-source, freely available database of human biological pathways and processes. A major goal of our work is to provide an integrated view of cellular signalling processes that spans from ligand–receptor interactions to molecular readouts at the level of metabolic and transcriptional events. To this end, we have built the first catalogue of all human G protein-coupled receptors (GPCRs) known to bind endogenous or natural ligands. The UniProt database has records for 797 proteins classified as GPCRs and sorted into families A/1, B/2 and C/3 on the basis of amino accid sequence. To these records we have added details from the IUPHAR database and our own manual curation of relevant literature to create reactions in which 563 GPCRs bind ligands and also interact with specific G-proteins to initiate signalling cascades. We believe the remaining 234 GPCRs are true orphans. The Reactome GPCR pathway can be viewed as a detailed interactive diagram and can be exported in many forms. It provides a template for the orthology-based inference of GPCR reactions for diverse model organism species, and can be overlaid with protein–protein interaction and gene expression datasets to facilitate overrepresentation studies and other forms of pathway analysis

Toward a multiscale modeling framework for understanding serotonergic function

Despite its importance in regulating emotion and mental wellbeing, the complex structure and function of the serotonergic system present formidable challenges toward understanding its mechanisms. In this paper, we review studies investigating the interactions between serotonergic and related brain systems and their behavior at multiple scales, with a focus on biologically-based computational modeling. We first discuss serotonergic intracellular signaling and neuronal excitability, followed by neuronal circuit and systems levels. At each level of organization, we will discuss the experimental work accompanied by related computational modeling work. We then suggest that a multiscale modeling approach that integrates the various levels of neurobiological organization could potentially transform the way we understand the complex functions associated with serotonin

Expression, pharmacology and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages

Somatostatin (SRIF)-14 is recognized as an important mediator between the nervous and the immune system, although the functional role of its receptors (sst1-sst5) is poorly understood in humans. In our study, we demonstrate that human macrophages differentiated from peripheral blood mononuclear cell-derived monocytes express both sst1 and sst2 mRNAs. Both sst1 and sst2 are mostly localized at the cell surface and display active binding sites. In particular, sst1/sst2 activation results in a weak internalization of sst1 while the sst2 internalization appears more efficient. At the functional level, the activation of SRIF receptors by the multiligand analogues SOM230 and KE108, but not by SRIF-14 or cortistatin-14, reduces macrophage viability. Their effects are mimicked by the selective activation of sst1 and sst2 using CH-275 and SMS 201-995/L-779,976, respectively. Further, both sst1- and sst2-mediated effects are reversed by the sst1 antagonist SRA-880 or the sst2 antagonist CYN, respectively. CH-275, SMS 201-995 and L-779,976, but not SRIF-14, decrease both mRNA expression and secretion of the monocyte chemotactic protein-1. In addition, SRIF-14, CH-275, SMS 201-995 and L-779,976 decrease interleukine-8 secretion while they do not affect interleukine-8 mRNA expression. In contrast, SRIF-14 and sst1/sst2 agonists do not affect the secretion of matrix metalloproteinase-9. Collectively, our results suggest that the SRIF system, through sst1 and sst2, exerts mainly an immunosuppressive effect in human macrophages and may, therefore, represent a therapeutic window that can be exploited for the development of new strategies in pharmacological therapy of inflammation.L'articolo è disponibile sul sito dell'editore http://leukocytebiology.org/default.asp

RhoA GTPase inhibition organizes contraction during epithelial morphogenesis

During morphogenesis, contraction of the actomyosin cytoskeleton within individual cells drives cell shape changes that fold tissues. Coordination of cytoskeletal contractility is mediated by regulating RhoA GTPase activity. Guanine nucleotide exchange factors (GEFs) activate and GTPase-activating proteins (GAPs) inhibit RhoA activity. Most studies of tissue folding, including apical constriction, have focused on how RhoA is activated by GEFs to promote cell contractility, with little investigation as to how GAPs may be important. Here, we identify a critical role for a RhoA GAP, Cumberland GAP (C-GAP), which coordinates with a RhoA GEF, RhoGEF2, to organize spatiotemporal contractility during Drosophila melanogaster apical constriction. C-GAP spatially restricts RhoA pathway activity to a central position in the apical cortex. RhoGEF2 pulses precede myosin, and C-GAP is required for pulsation, suggesting that contractile pulses result from RhoA activity cycling. Finally, C-GAP expression level influences the transition from reversible to irreversible cell shape change, which defines the onset of tissue shape change. Our data demonstrate that RhoA activity cycling and modulating the ratio of RhoGEF2 to C-GAP are required for tissue folding.American Cancer Society (125792-RSG-14-039-01-CSM

Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25

Thymic T cell progenitor (TCP) importation is a periodic, gated event that is dependent on the expression of functional P-selectin ligands on TCPs. Occupancy of intrathymic TCP niches is believed to negatively regulate TCP importation, but the nature of this feedback mechanism is not yet resolved. We show that P-selectin and CCL25 are periodically expressed in the thymus and are essential parts of the thymic gate-keeping mechanism. Periodicity of thymic TCP receptivity and the size of the earliest intrathymic TCP pool were dependent on the presence of functional P-selectin ligand on TCPs. Furthermore, we show that the numbers of peripheral blood lymphocytes directly affected thymic P-selectin expression and TCP receptivity. We identified sphingosine-1-phosphate (S1P) as one feedback signal that could mediate influence of the peripheral lymphocyte pool on thymic TCP receptivity. Our findings suggest a model whereby thymic TCP importation is controlled by both early thymic niche occupancy and the peripheral lymphocyte pool via S1P