1,720,984 research outputs found
Trypanosoma cruzi trans-sialidase induces STAT3 and ERK activation by prokineticin receptor 2 binding
No full textTc85, as other members of trans-sialidase family, is involved in Trypanosoma cruzi parasite adhesion to mammalian cells. Particularly, Tc85 acts through specific interactions with prokineticin receptor 2, a G-protein coupled receptor involved in diverse physiological and pathological processes. In this manuscript, through biochemical analyses, we demonstrated that LamG, a Tc85 domain, physically interacts with the prokineticin receptor 2. Moreover, expressing prokineticin receptor 1 and 2 we demonstrated that LamG specifically activates prokineticin receptor 2 through a strong coupling with Gαi or Gαq proteins in yeast strains and inducing ERK and NFAT phosphorylation in CHO mammalian cells. To demonstrate a Tc85 physiological role in T. cruzi infection of the nervous system, we evidenced a strong STAT3 and ERK activation by LamG in mice Dorsal Root Ganglia. L173R is the most common prokineticin receptor 2 mutation reported in Kallmann syndrome and it is a founder mutation. Our results demonstrated that in cells co-expressing prokineticin receptor 2 mutant (L173R) and wild-type, LamG is unable to induce signal transduction. The L173R mutation in heterozygosity may allow for a selective advantage due to increased protection from T. cruzi infection. Significance of the study: The Chagas' disease affecting millions of people worldwide is caused by an eukaryotic microorganism called T. cruzi. Pharmacological treatment for patients with Chagas' disease is still limited. Indeed, the small number of drugs available shows important side effects that can be debilitating for patient health. In order to replicate and produce new parasites T. cruzi uses a complex of different proteins produced by both the parasite and the human host cells. So, understanding the molecular details used by T. cruzi to be internalised by different types of human cells is an important step towards the development of new drugs for this disease. Prokineticin receptors are relevant for host-parasite interaction. To characterise the signal transduction cascade induced by their activation may help to understand the molecular details of cell infection, leading to novel therapeutic alternative for this debilitating disease
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Controlling the activation of the prokineticin system as therapeutic approach to relief neuropathic pain and reduce neuroinflammation
No full textNeuropathic pain is a relevant clinical problem worldwide, since current therapeutic treatments are unsatisfactory. The identification of novel therapeutic targets and the development of new pharmacological approaches remain a priority. This pathological condition is generally triggered by an injury at peripheral or central nervous system and it is characterized by pain exacerbation and neuronal hypersensitization, resulting in abnormal pain transmission. Neuroinflammation in the peripheral and central nervous system largely contributes to neuropathic pain onset, development and maintenance. In this scenario, the recently identified chemokine family, the prokineticin system (PKS), is a promising pharmacological target for the management of neuropathic pain, considering its pronociceptive and proinflammatory properties and its role in neuronal-glia interaction. Moreover, the availability of specific receptor antagonists makes this system even more interesting in order to control prokineticin activity. In this review we report all preclinical data available on the role of PKS in the physiopathology of neuropathic pain. The results clearly suggest that drugs which block the PKS may represent an innovative and efficacious pharmacological treatment to control neuropathic pain in patients
Identification and characterization of a new splicing variant of prokineticin 2
Full text linkProkineticin 2 (PROK2) is a secreted bioactive peptide that regulates a variety of biological responses via two GPCRs, the prokineticin receptors (PROKRs). The aim of this study was to characterize a new alternatively spliced product of the prok2 gene consisting of four exons. The 40-amino acid peptide, designated PROK2C, is encoded by exon 1 and exon 4, and its expression was detected in the hippocampus and spinal cord of mice. PROK2C was expressed in a heterologous system, Pichia pastoris, and its binding specificity to the amino-terminal regions of PROKR1 and PROKR2 was investigated by GST pull-down experiments. In addition, the introduction of the unnatural amino acid p-benzoyl-L-phenylalanine using amber codon suppression technology demonstrated the role of tryptophan at position 212 of PROKR2 for PROK2C binding by photoactivatable cross-linking. The functional significance of this new isoform was determined in vivo by nociceptive experiments, which showed that PROK2C elicits strong sensitization of peripheral nociceptors to painful stimuli. In order to analyze the induction of PROK2C signal transduction, STAT3 and ERK phosphorylation levels were determined in mammalian CHO cells expressing PROKR1 and PROKR2. Our data show by in vivo and in vitro experiments that PROK2C can bind and activate both prokineticin receptors
Arginine 125 is an essential residue for the function of MRAP2
Full text linkMRAP2 is a small simple transmembrane protein arranged in a double antiparallel topology
on the plasma membrane. It is expressed in the paraventricular nucleus of the hypothalamus, where
it interacts with various G protein-coupled receptors, such as the prokineticin receptors, and regulates
energy expenditure and appetite. The aim of this work was to analyze the functional role of the specific
arginine residue at position 125 of MRAP2, which affects protein conformation, dimer formation,
and PKR2 binding. Results obtained with the MRAP2 mutants R125H and R125C, which are found
in human patients with extreme obesity, and mouse MRAP2, in which arginine 125 is normally
replaced by histidine, were compared with those obtained with human MRAP2. Understanding
the mechanism by which MRAP2 regulates G protein-coupled receptors helps in elucidating the
metabolic pathways involved in metabolic dysfunction and in developing new drugs as specific
targets of the MRAP2-PKR2 complex
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Abnormal pain sensation in mice lacking the prokineticin receptor PKR2: interaction of PKR2 with transient receptor potential TRPV1 and TRPA1
Full text linkThe amphibian Bv8 and the mammalian prokineticin 1 (PROK1) and 2 (PROK2) are new chemokine-like protein ligands acting on two G protein-coupled receptors, prokineticin receptor 1 (PKR1) and 2 (PKR2), participating to the mediation of diverse physiological and pathological processes. Prokineticins (PKs), specifically activating the prokineticin receptors (PKRs) located in several areas of the central and peripheral nervous system associated with pain, play a fundamental role in nociception. In this paper, to improve the understanding of the prokineticin system in the neurobiology of pain, we investigated the role of PKR2 in pain perception using pkr2 gene-deficient mice. We observed that, compared to wildtype, pkr2-null mice were more resistant to nociceptive sensitization to temperatures ranging from 46 to 48 °C, to capsaicin and to protons, highlighting a positive interaction between PKR2 and the non-selective cation channels TRPV1. Moreover, PKR2 knock-out mice showed reduced nociceptive response to cold temperature (4 °C) and to mustard oil-induced inflammatory hyperalgesia, suggesting a functional interaction between PKR2 and transient receptor potential ankyrin 1 ion (TRPA1) channels. This notion was supported by experiments in dorsal root ganglia (DRG) cultures from pkr1 and–pkr2-null mice, demonstrating that the percentage of Bv8-responsive DRG neurons which were also responsive to mustard oil was much higher in PKR1−/− than in PKR2−/− mice. Taken together, these findings suggest a functional interaction between PKR2 and TRP channels in the development of hyperalgesia. Drugs able to directly or indirectly block these targets and/or their interactions may represent potential analgesics
MRAP2 inhibits β-arrestin-2 recruitment to the Prokineticin 2 receptor 2
No full textMelanocortin receptor accessory protein 2 (MRAP2) is a membrane protein that binds 11 multiple G protein-coupled receptors (GPCRs), involved in the control of energy homeostasis in- 12 cluding prokineticin receptors. These GPCRs are expressed both centrally and peripherally and 13 their endogenous ligands are prokineticin 1 (PK1) and prokineticin 2 (PK2). PKRs couple all G-pro- 14 tein subtypes such as Gαq/11, Gαs and Gαi and recruit β-arrestins upon PK2 stimulation, although 15 the interaction between PKR2 and β-arrestins does not trigger receptor internalisation. MRAP2 in- 16 hibits the anorexigenic effect of PK2 by binding PKR1 and PKR2. The aim of this work was to eluci- 17 date the role of MRAP2 in modulating PKR2-induced β-arrestin-2 recruitment and β-arrestin-medi- 18 ated signalling. This study could allow the identification of new specific targets for potential new 19 drugs useful for the treatment of the various pathologies correlated with prokineticin, in particular 20 obesity
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