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P2 Receptors

Anna I Erdei, Adina Borbély, Anna Magyar, Edina Szűcs, Ferenc Ötvös, Dávid Gombos, Mahmoud Al-Khrasani, Azzurra Stefanucci, Marilisa Pia Dimmito, Grazia Luisi, Adriano Mollica, Sándor Benyhe
The endogenous ligand nociceptin (N/OFQ) and a positively charged synthetic peptide RYYRIK are both selective for the nociceptin opioid receptor (NOPr). Despite their structural dissimilarity, N/OFQ and RYYRIK compete for the same binding site of NOP receptor possessing full and partial agonistic character, respectively. In the view of the message-address concept, hybrid peptide constructs were probed for the NOP receptor combining different regions of N/OFQ and RYYRIK related peptide sequences. Nine novel nociceptin- or Ac-RYYRIK-NH2 peptide variants or hybrid peptides were synthesized and characterized...
December 1, 2018: Peptides
Andréia Machado Cardoso, Leandro Henrique Manfredi, Daniela Zanini, Margarete Dulce Bagatini, Jessié Martins Gutierres, Fabiano Carvalho, Alain Tremblay, Adriane Belló-Klein, Maribel Antonello Rubin, Vera Maria Morsch, Jean Sévigny, Maria Rosa Chitolina Schetinger
: Background: Central nervous system function has been emerging as an approach to understand hypertension-mediated memory dysfunction, and chronic exercise is able to modulate the purinergic system. METHOD: Herein, we investigated the effect of chronic swimming training on the purinergic system in cortex and hippocampus of L-NAME-induced hypertensive rats. Male Wistar rats were divided into four groups: Control, Exercise, L-NAME and Exercise L-NAME. Inhibitory avoidance test was used to assess memory status...
January 2019: Journal of Hypertension
Lena O Jones, James L Stafford
Cells of the innate immune system rapidly detect and eliminate invading microbes using surface-expressed immunoregulatory receptors that translate extracellular binding events into potent effector responses. Channel catfish leukocyte immune-type receptors (IpLITRs) are a family of immunoregulatory proteins that have been shown to regulate several innate immune cell effector responses including the phagocytic process. The mechanisms by which these receptors regulate phagocytosis are not entirely understood but we have previously shown that different IpLITR-types use ITAM-dependent as well as ITAM-independent pathways for controlling target engulfment...
November 29, 2018: Developmental and Comparative Immunology
M Domercq, A Zabala, C Matute
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, characterized by the presence of focal lesions in white and grey matter with peripheral immune cells infiltration. Purinergic receptors control immune cell function as well as neuronal and oligodendroglial survival, and the activation of astrocytes and microglia, the endogenous brain immune cells. In particular, ionotropic purinergic receptors P2X4 and P2X7 and metabotropic receptor P2Y12 are differently expressed along the disease and their activation or blockage modifies the course of texperimental autoimmune encephalomyelitis (EAE), the dominant animal model of MS...
November 27, 2018: Brain Research Bulletin
Elena Petukhova, Daria Ponomareva, Marat Mukhamedyarov, Galyna Maleeva, Piotr Bregestovski
Mammalian brainstem hypoglossal motoneurones (HMs) receive powerful synaptic glycinergic inputs and are involved in a variety of motor functions, including respiration, chewing, sucking, swallowing, and phonation. During the early postnatal development, subunit composition of chloride-permeable glycine receptors (GlyRs) changes leading to a decrease of "fetal" alpha2 and elevation of "adult" alpha1 GlyR subunits. It has been recently demonstrated that niflumic acid (NFA), a member of the fenamate class of non-steroidal anti-inflammatory drugs, is an efficient subunits-specific blocker of GlyRs...
2018: Frontiers in Molecular Neuroscience
Byeongjae Chun, Bradley D Stewart, Darin D Vaughan, Adam D Bachstetter, Peter M Kekenes-Huskey
KEY POINTS SUMMARY: • A computational model of P2X channel activation in microglia was developed that includes downfield Ca2+ dependent signaling pathways. • This model provides quantitative insights into how diverse signaling pathways in microglia converge to control microglial function. ABSTRACT: Microglia function is orchestrated through highly-coupled signaling pathways that depend on calcium (Ca2+). In response to extracellular adeno- sine triphosphate (ATP), transient increases in intracellular Ca2+ driven through the activation of purinergic receptors, P2X and P2Y, are sufficient to promote cytokine synthesis...
November 21, 2018: Journal of Physiology
Yong Tang, Hai-Yan Yin, Juan Liu, Patrizia Rubini, Peter Illes
Purinergic signaling has recently been suggested to constitute the cellular mechanism underlying acupuncture-induced analgesia (AA). By extending the original hypothesis on endogenous opioids being released during AA, Geoffrey Burnstock and Maiken Nedergaard supplied evidence for the involvement of purinoceptors (P2 and P1/A1 receptors) in the beneficial effects of AA. In view of certain pain states (e.g. neuropathic pain) which respond only poorly to therapy with standard analgesics, as well as with respect to the numerous unwanted effects of opioids and non-steroidal anti-inflammatory drugs, it is of great significance to search for alternative therapeutic options...
November 17, 2018: Brain Research Bulletin
Anna Lisa Giuliani, Alba Clara Sarti, Francesco Di Virgilio
Extracellular nucleotides, mainly ATP, but also ADP, UTP, UDP and UDP-sugars, adenosine, and adenine base participate in the "purinergic signalling" pathway, an ubiquitous system of cell-to-cell communication. Fundamental pathophysiological processes such as tissue homeostasis, wound healing, neurodegeneration, immunity, inflammation and cancer are modulated by purinergic signalling. Nucleotides can be released from cells via unspecific or specific mechanisms. A non-regulated nucleotide release can occur from damaged or dying cells, whereas exocytotic granules, plasma membrane-derived microvesicles, membrane channels (connexins, pannexins, calcium homeostasis modulator (CALHM) channels and P2X7 receptor) or specific ATP binding cassette (ABC) transporters are involved in the controlled release...
November 12, 2018: Immunology Letters
Oleg Palygin, Daria V Ilatovskaya, Vladislav Levchenko, Christine A Klemens, Lashodya Dissanayake, Anna Marie Williams, Tengis S Pavlov, Alexander Staruschenko
Polycystic kidney diseases (PKDs) are a group of inherited nephropathies marked by formation of fluid-filled cysts along the nephron. Growing evidence suggests that in the kidney formation of cysts and alteration of cystic electrolyte transport are associated with purinergic signaling. PCK/CrljCrl-Pkhd1pck/CRL (PCK) rat, an established model of autosomal recessive polycystic kidney disease (ARPKD), was used here to test this hypothesis. Cystic fluid of PCK rats and their cortical tissues exhibited significantly higher levels of ATP compared to Sprague Dawley rat kidney cortical interstitium as assessed by highly sensitive ATP enzymatic biosensors...
November 11, 2018: Purinergic Signalling
Christopher J Penny, Kristin Vassileva, Archana Jha, Yu Yuan, Xavier Chee, Elizabeth Yates, Michela Mazzon, Bethan S Kilpatrick, Shmuel Muallem, Mark Marsh, Taufiq Rahman, Sandip Patel
Two-pore channels (TPCs) are Ca2+ -permeable ion channels localised to the endo-lysosomal system where they regulate trafficking of various cargoes including viruses. As a result, TPCs are emerging as important drug targets. However their pharmacology is ill-defined. There are no approved drugs to target them. And their mechanism of ligand activation is largely unknown. Here, we identify a number of FDA-approved drugs as TPC pore blockers. Using a model of the pore of human TPC2 based on recent structures of mammalian TPCs, we virtually screened a database of ~1500 approved drugs...
November 5, 2018: Biochimica et biophysica acta. Molecular cell research
Colin D H Ratcliffe, Nadeem Siddiqui, Paula P Coelho, Nancy Laterreur, Tumini N Cookey, Nahum Sonenberg, Morag Park
Differential inclusion or skipping of microexons is an increasingly recognized class of alternative splicing events. However, the functional significance of microexons and their contribution to signaling diversity is poorly understood. The Met receptor tyrosine kinase (RTK) modulates invasive growth and migration in development and cancer. Here, we show that microexon switching in the Arf6 guanine nucleotide exchange factor cytohesin-1 controls Met-dependent cell migration. Cytohesin-1 isoforms, differing by the inclusion of an evolutionarily conserved three-nucleotide microexon in the pleckstrin homology domain, display differential affinity for PI(4,5)P2 (triglycine) and PI(3,4,5)P3 (diglycine)...
November 7, 2018: Journal of Cell Biology
Liyanage Manosika Buddhini Perera, Akiko Sekiguchi, Akihiko Uchiyama, Akihito Uehara, Chisako Fujiwara, Sahori Yamazaki, Yoko Yokoyama, Sachiko Ogino, Ryoko Torii, Mari Hosoi, Osamu Ishikawa, Sei-Ichiro Motegi
Tissue injury/hypoxia and oxidative stress induced-extracellular ATP can act as a damage-associated molecular pattern molecules (DAMPs), which initiates inflammatory response. Objective was to elucidate the role of extracellular ATP in skin fibrosis in systemic sclerosis (SSc). We identified that hypoxia enhanced ATP release, and extracellular ATP enhanced IL-6 production more significantly in SSc fibroblasts than in normal fibroblasts. There were no significant differences of P2X and P2Y receptors expressions between normal and SSc fibroblasts...
November 4, 2018: Journal of Investigative Dermatology
Cyrill Schipp, David Schlütermann, Andrea Hönscheid, Schafiq Nabhani, Jessica Höll, Prasad T Oommen, Sebastian Ginzel, Bernhard Fleckenstein, Björn Stork, Arndt Borkhardt, Polina Stepensky, Ute Fischer
Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous STK4 mutations...
2018: Frontiers in Immunology
Hongliu Sun, Luyu Ma, Yurong Zhang, Xiaohong Pan, Chaoyun Wang, Jinjin Zhang, Xiuli Zhang, Hongwei Sun, Qiaoyun Wang, Wei Zhu
Previous studies suggested that the thrombospondin-1/transforming growth factor-β1 (TSP-1/TGF-β1) pathway might be critical in synaptogenesis during development and that the purinergic P2 receptor family could regulate synaptogenesis by modulating TSP-1 signaling. However, it is unclear whether this pathway plays a role in synaptogenesis during epileptic progression. This study was designed to investigate this question by analyzing the dynamic changes and effects of TSP-1 levels on the density of synaptic markers that are related to epileptic seizure activity...
2018: Frontiers in Cellular Neuroscience
Claudio Coddou, Rodrigo Sandoval, María José Hevia, Stanko S Stojilkovic
P2X receptors (P2XRs) are a family of ATP-gated ionic channels that are expressed in numerous excitable and non-excitable cells. Despite the great advance on the structure and function of these receptors in the last decades, there is still lack of specific and potent antagonists for P2XRs subtypes, especially for the P2X4R. Here, we studied in detail the effect of the P2X4R antagonist 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) on ATP-induced currents mediated by the rat P2X4R and compared its specificity among another rat P2XRs...
October 23, 2018: Neuroscience Letters
Eilidh Craigie, Robert I Menzies, Casper K Larsen, Grégory Jacquillet, Monique Carrel, Scott S Wildman, Johannes Loffing, Jens Leipziger, David G Shirley, Matthew A Bailey, Robert J Unwin
In the kidney, purinergic (P2) receptor-mediated ATP signaling has been shown to be an important local regulator of epithelial sodium transport. Appropriate sodium regulation is crucial for blood pressure (BP) control and disturbances in sodium balance can lead to hypo- or hypertension. Links have already been established between P2 receptor signaling and the development of hypertension, attributed mainly to vascular and/or inflammatory effects. A transgenic mouse model with deletion of the P2X4 receptor (P2X4-/- ) is known to have hypertension, which is thought to reflect endothelial dysfunction and impaired nitric oxide (NO) release...
October 2018: Physiological Reports
Ruixin Zhang, Xuze Qin, Ting Zhang, Qian Li, Jianxin Zhang, Junxing Zhao
Astragalus polysaccharide (APS) is an important bioactive component of Astragalus membranaceus which is used as an anti-diabetes herb in traditional Chinese medicine. The objective of this study was to investigate the effects and mechanisms of APS on insulin-sensitizing of adipocytes. Mouse 3T3-L1 preadipocytes were used as a model. The results showed that APS increased preadipocytes proliferation in a dose dependent manner, and 0.1 μg/mL APS sufficiently increased Proliferating Cell Nuclear Antigen (PCNA) content ( p < 0...
October 21, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Yuichiro Fukumoto, Kenji F Tanaka, Bijay Parajuli, Keisuke Shibata, Hideyuki Yoshioka, Kazuya Kanemaru, Christian Gachet, Kazuhiro Ikenaka, Schuichi Koizumi, Hiroyuki Kinouchi
Extracellular ATP, which is released from damaged cells after ischemia, activates P2 receptors. P2Y1 receptors (P2Y1 R) have received considerable attention, especially in astrocytes, because their activation plays a central role in the regulation of neuron-to-glia communication. However, the functions or even existence of P2Y1 R in microglia remain unknown, despite the fact that many microglial P2 receptors are involved in several brain diseases. Herein, we demonstrate the presence and functional capability of microglial P2Y1 R to provide neuroprotective effects following ischemic stress...
October 18, 2018: Journal of Cerebral Blood Flow and Metabolism
Piotr Sirko, Jonathan E Gale, Jonathan F Ashmore
Intercellular Ca2+ waves are increases in cytoplasmic Ca2+ levels that propagate between cells Periodic Ca2+ waves have been linked to gene regulation and are thought to play a crucial role in the development of our hearing epithelium the organ of Corti and the acquisition of hearing We have observed regular periodic intercellular Ca2+ waves in supporting cells of an ex vivo preparation of the adult mouse organ of Corti, the waves were found to propagate independently of extracellular ATP and were inhibited by the gap junction blockers 1-octanol and carbenoxolone...
October 15, 2018: Journal of Physiology
Ramin Lotfi, Lena Steppe, Regina Hang, Markus Rojewski, Marina Massold, Bernd Jahrsdörfer, Hubert Schrezenmeier
INTRODUCTION: MSCs are often found within tumors, promote cancer progression and enhance metastasis. MSCs can act as immuosuppressive cells, partially due to the expression of the enzyme indoleamine dioxygenase (IDO) which converts tryptophan to kynurenine. Decreased concentration of tryptophan and increased kynurenine, both interfere with effective immune response. Damage associated molecular patterns (DAMPs) including ATP are found within the tumor microenvironment, attract MSCs, and influence their biology...
December 2018: Immunity, Inflammation and Disease
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