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Endogenous Ligand (endogenous + ligand)
Selected AbstractsNeuropharmacology and therapeutic potential of cannabinoidsADDICTION BIOLOGY, Issue 1 2000Roger G. Pertwee Mammalian tissues contain at least two types of cannabinoid receptor, CB 1, found mainly on neurones and CB 2, found mainly in immune cells. Endogenous ligands for these receptors have also been identified. These endocannabinoids and their receptors constitute the endogenous cannabinoid system. Two cannabinoid receptor agonists, ,9 -tetrahydrocannabinol and nabilone, are used clinically as anti-emetics or to boost appetite. Additional therapeutic uses of cannabinoids may include the suppression of some multiple sclerosis and spinal injury symptoms, the management of pain, bronchial asthma and glaucoma, and the prevention of neurotoxicity. There are also potential clinical applications for CB 1 receptor antagonists, in the management of acute schizophrenia and cognitive/memory dysfunctions and as appetite suppressants. Future research is likely to be directed at characterizing the endogenous cannabinoid system more completely, at obtaining more conclusive clinical data about cannabinoids with regard to both beneficial and adverse effects, at developing improved cannabinoid formulations and modes of administration for use in the clinic and at devising clinical strategies for separating out the sought-after effects of CB 1 receptor agonists from their psychotropic and other unwanted effects. [source] Growth hormone secretagogue receptor antagonists as potential therapeutic agents for obesityDRUG DEVELOPMENT RESEARCH, Issue 2 2005Hongyu Zhao Abstract Safe and efficacious medicines for obesity treatment are greatly needed. As an endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R 1a), ghrelin is the only known circulating orexigen. Administration of ghrelin causes food intake and body weight increase in both rodents and humans, whereas inhibiting its actions by antibodies, peptide antagonists, and anti-sense oligonucleotides leads to decreased food intake and weight loss. Recent progress in developing nonpeptidyl small molecule GHS-R antagonists is reviewed in this article. Drug Dev. Res. 65:50,54, 2005. © 2005 Wiley-Liss, Inc. [source] Vascular effects of adenosine and its analoguesDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Debbie Prentice Abstract The main action of adenosine on vascular beds is vasodilation via A2 receptors. In addition, A1 receptors are found in some blood vessels, where they cause contraction. Traditionally, adenosine-induced vasodilation in vitro has been attributed to A2A receptor activation; however, it is now clear that A2B receptors are also involved in the regulation of vascular tone. Endothelium dependence of A2 receptor-mediated responses is variable; in some tissues they are blocked by removal of endothelium and/or inhibition of NO-synthase and in some they are not. In addition to A2 receptor-mediated relaxation, there is much evidence that relaxations to adenosine and some of its analogues can also be mediated by a mechanism which cannot be blocked by adenosine receptor antagonists. There is evidence that these responses are endothelium- and NO-independent and that, under conditions where adenosine is taken up into cells, relaxations to the endogenous ligand are entirely mediated by this mechanism, suggesting it is of physiological significance. Drug Dev. Res. 52:346,349, 2001. © 2001 Wiley-Liss, Inc. [source] Effects of the androgenic growth promoter 17-,-trenbolone on fecundity and reproductive endocrinology of the fathead minnow,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 6 2003Gerald T. Ankley Abstract Trenbolone acetate is a synthetic steroid that is extensively used in the United States as a growth promoter in beef cattle. The acetate is administered to livestock via slow-release implants; some is converted by the animal to 17-,-trenbolone, a relatively potent androgen receptor agonist in mammalian systems. Recent studies indicate that excreted 17-,-trenbolone is comparatively stable in animal waste, suggesting the potential for exposure to aquatic animals via direct discharge, runoff, or both. However, little is known concerning the toxicity of trenbolone to fish. Our goal was to assess the effects of 17-,-trenbolone on reproductive endocrinology of the fathead minnow (Pimephales promelas). An in vitro competitive binding study with the fathead minnow androgen receptor demonstrated that 17-,-trenbolone had a higher affinity for the receptor than that of the endogenous ligand, testosterone. Male and female fish were exposed for 21 d to nominal (target) concentrations of 17-,-trenbolone ranging from 0.005 to 50 ,g/L. Fecundity of the fish was significantly reduced by exposure to measured test concentrations , 0.027 ,g/ L. The 17-,-trenbolone was clearly androgenic in vivo at these concentrations, as evidenced by the de novo production in females of dorsal (nuptial) tubercles, structures normally present only on the heads of mature males. Plasma steroid (testosterone and ,-estradiol) and vitellogenin concentrations in the females all were significantly reduced by exposure to 17-,-trenbolone. The 17-,-trenbolone also altered reproductive physiology of male fathead minnows, albeit at concentrations much higher than those producing effects in females. Males exposed to 17-,-trenbolone at 41 ,g/L (measured) exhibited decreased plasma concentrations of 11-ketotestosterone and increased concentrations of ,-estradiol and vitellogenin. Overall, our studies indicate that 17-,-trenbolone is a potent androgen and reproductive toxicant in fish. Given the widespread use of trenbolone acetate as a growth promoter, and relative stability of its metabolites in animal wastes, further studies are warranted to assess potential ecological risk. [source] The DC-SIGN family member LSECtin is a novel ligand of CD44 on activated T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010Li Tang LSECtin, a novel member of the C-type lectin DC-SIGN family, not only acts as an attachment factor for pathogens, but also recognizes "endogenous" activated T cells. The endogenous ligands of LSECtin, however, have remained unclear. In this study, we identified CD44 on Jurkat T cells as a candidate ligand of LSECtin, and confirmed the specific interaction between LSECtin and CD44. Moreover, we showed that LSECtin selectively bound CD44s, CD44v4 and CD44v8-10 by screening a series of typical CD44 isoforms. By deletion of the carbohydrate-recognition domain region and mutation of crucial amino acids involved in carbohydrate-recognition of LSECtin and by inhibition of the N-linked glycosylation of CD44, we further demonstrated that the interaction between CD44 and LSECtin is dependent on protein-glycan recognition. Our findings indicate that CD44 is the first identified endogenous ligand of LSECtin, and similarly, that LSECtin is a novel ligand of CD44. These findings provide important new perspectives on the biology of both LSECtin and CD44 in the immune system. [source] Development and maturation of invariant NKT cells in the presence of lysosomal engulfmentEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009Tiziana Plati Abstract A defect in invariant NKT (iNKT) cell selection was hypothesized in lysosomal storage disorders (LSD). Accumulation of glycosphingolipids (GSL) in LSD could influence lipid loading and/or presentation causing entrapment of endogenous ligand(s) within storage bodies or competition of the selecting ligand(s) by stored lipids for CD1d binding. However, when we analyzed the iNKT cell compartment in newly tested LSD animal models that accumulate GSL, glycoaminoglycans or both, we observed a defective iNKT cell selection only in animals affected by multiple sulfatase deficiency, in which a generalized aberrant T-cell development, rather than a pure iNKT defect, was present. Mice with single lysosomal enzyme deficiencies had normal iNKT cell development. Thus, GSL/glycoaminoglycans storage and lysosomal engulfment are not sufficient for affecting iNKT cell development. Rather, lipid ligand(s) or storage compounds, which are affected in those LSD lacking mature iNKT cells, might indeed be relevant for iNKT cell selection. [source] Functional characterization of a neuropeptide F-like receptor from Drosophila melanogasterEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2003Guoping Feng Abstract A cDNA clone encoding a seven-transmembrane domain, G-protein-coupled receptor (NPFR76F, also called GPCR60), has been isolated from Drosophila melanogaster. Deletion mapping showed that the gene encoding this receptor is located on the left arm of the third chromosome at position 76F. Northern blotting and whole mount in situ hybridization have shown that this receptor is expressed in a limited number of neurons in the central and peripheral nervous systems of embryos and adults. Analysis of the deduced amino acid sequence suggests that this receptor is related to vertebrate neuropeptide Y receptors. This Drosophila receptor shows 62,66% similarity and 32,34% identity to type 2 neuropeptide Y receptors cloned from a variety of vertebrate sources. Coexpression in Xenopus oocytes of NPFR76F with the promiscuous G-protein G,16 showed that this receptor is activated by the vertebrate neuropeptide Y family to produce inward currents due to the activation of an endogenous oocyte calcium-dependent chloride current. Maximum receptor activation was achieved with short, putative Drosophila neuropeptide F peptides (Drm-sNPF-1, 2 and 2s). Neuropeptide F-like peptides in Drosophila have been implicated in a signalling system that modulates food response and social behaviour. The identification of this neuropeptide F-like receptor and its endogenous ligand by reverse pharmacology will facilitate genetic and behavioural studies of neuropeptide functions in Drosophila. [source] Strain differences in ,1 receptor-mediated behaviours are related to neurosteroid levelsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2002Vân-Ly Phan Abstract The sigma1 (,1) receptor exerts a potent neuromodulatory role in the brain with relevant consequences in memory processes, response to stress, depression and pharmacodependence. Its precise endogenous ligand is not yet identified but the ,1 receptor appears to be one target for the nongenomic rapid effects of neuroactive steroids in the brain. The aim of the present study was to establish whether differences in ,1 receptor-mediated behaviours could be observed among mouse strains, in relation with differences in either ,1 receptor expression or steroid levels. The ,1 -receptor immunohistochemical distribution appeared similar between Swiss and C57BL/6 strains in all the brain structures examined. The levels of in vivo[3H](+)-SKF-10 047 binding to ,1 receptors were lower in Swiss than in C57BL/6. Adrenalectomy/castration significantly increased [3H](+)-SKF-10 047 binding only in Swiss. The behavioural efficacy of the selective ,1 agonists igmesine and PRE-084 , reversion of the scopolamine-induced amnesia in the passive avoidance test; diminution of the immobility duration in the forced swimming test , were significantly higher in C57BL/6 than in Swiss. Steroid levels were measured in the brain in basal conditions and after stress. C57BL/6 mice presented in both conditions, the lowest progesterone levels, this steroid acting as an endogenous ,1 antagonist. Collectively, the results suggested that strain differences in neuroactive steroid and particularly, progesterone, biosynthesis and sensitivity may contribute to the differential behavioural efficacy of ,1 -receptor ligands. Noteworthy, these observations are coherent with strain differences observed in the intensity of cocaine-induced reward properties, known to critically involve the ,1 receptor. [source] Toll-like receptors, endogenous ligands, and systemic autoimmune diseaseIMMUNOLOGICAL REVIEWS, Issue 1 2005Ian R. Rifkin Summary:, The critical role of Toll-like receptors (TLRs) as mediators of pathogen recognition by the innate immune system is now firmly established. Such recognition results in the initiation of an inflammatory immune response and subsequent instruction of the adaptive immune system, both of which are designed to rid the host of the invading pathogen. More controversial is the potential role of TLRs in the recognition of endogenous ligands and what effect this might have on the consequent development of autoimmune or other chronic sterile inflammatory disorders. An increasing number of studies implicate TLRs as being involved in the immune response to self-molecules that have in some way been altered from their native state or accumulate in non-physiologic sites or amounts, although questions have been raised about possible contaminants in certain of these studies. In this review, we discuss the evidence for endogenous ligand,TLR interactions with particular emphasis on mammalian chromatin, systemic lupus erythematosus, and atherosclerosis. Overall, the data support the general concept of a role for TLRs in the recognition of endogenous ligands. However, the precise details of the interactions and the extent to which they may contribute to the pathogenesis of human disease remain to be clarified. [source] 15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathwayINTERNATIONAL JOURNAL OF CANCER, Issue 5 2003George G. Chen Abstract Peroxisome proliferator-activated receptor gamma (PPAR,) inhibits cell growth via promoting apoptosis. Human colorectal cancer tissues had abundant PPAR, but the incidence of apoptosis was very low, suggesting a defect in the PPAR, pathway. Here, we found that 15-hydroxy-eicosatetraenoic acid (15S-HETE), an endogenous ligand for PPAR,, was significantly decreased in the serum of patients with colorectal cancer. Treatment of colon cancer cells with 15S-HETE inhibited cell proliferation and induced apoptosis, which was preceded by an increase in TGF-,-inducible early gene (TIEG) and a decrease in Bcl-2. The action of 15S-HETE could be blocked when PPAR, was suppressed. Overexpression of Bcl-2 prevented the apoptosis. The levels of TIEG and 15-lipoxygenase (15-LOX), the enzyme responsible for 15S-HETE production, was decreased in colorectal cancer. Therefore, colorectal cancer is associated with decreased 15S-HETE. Treatment of colon cancer cells with 15S-HETE inhibits cell proliferation and induces apoptosis in a PPAR,-dependent pathway involving augmentation of TIEG and reduction of Bcl-2 expression. © 2003 Wiley-Liss, Inc. [source] Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in ratsJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Marcello Solinas Abstract Although endogenous cannabinoid systems have been implicated in the modulation of the rewarding effects of abused drugs and food, little is known about the direct effects of endogenous ligands for cannabinoid receptors on brain reward processes. Here we show for the first time that the intravenous administration of anandamide, an endogenous ligand for cannabinoid receptors, and its longer-lasting synthetic analog methanandamide, increase the extracellular dopamine levels in the nucleus accumbens shell of awake, freely moving rats, an effect characteristic of most drugs abused by humans. Anandamide produced two distinctly different effects on dopamine levels: (1) a rapid, transient increase that was blocked by the cannabinoid CB1 receptor antagonist rimonabant, but not by the vanilloid VR1 receptor antagonist capsazepine, and was magnified and prolonged by the fatty acid amide hydrolase (FAAH) enzyme inhibitor, URB597; (2) a smaller delayed and long-lasting increase, not sensitive to CB1, VR1 or FAAH blockade. Both effects were blocked by infusing either tetrodotoxin (TTX, 1 µm) or calcium-free Ringer's solution through the microdialysis probe, demonstrating that they were dependent on the physiologic activation of dopaminergic neurotransmission. Thus, these results indicate that anandamide, through the activation of the mesolimbic dopaminergic system, participates in the signaling of brain reward processes. [source] Evidence for a Stimulatory Action of Melanin-Concentrating Hormone on Luteinising Hormone Release Involving MCH1 and Melanocortin-5 ReceptorsJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2006J. F. Murray Abstract The present series of studies aimed to further our understanding of the role of melanin-concentrating hormone (MCH) neurones in the central regulation of luteinising hormone (LH) release in the female rat. LH release was stimulated when MCH was injected bilaterally into the rostral preoptic area (rPOA) or medial preoptic area (mPOA), but not when injected into the zona incerta (ZI), of oestrogen-primed ovariectomised rats. In rats that were steroid-primed to generate a surge-like release of LH, MCH administration into the ZI blocked this rise in LH release: no such effect occurred when MCH was injected into the rPOA or mPOA. In vitro, MCH stimulated gonadotrophin-releasing hormone (GnRH) release from hypothalamic explants. Double-label immunohistochemistry showed GnRH-immunoreactive neurones in the vicinity of and intermingled with immunoreactive MCH processes. MCH is the endogenous ligand of the MCH type 1 receptor (MCH1-R). Previously, we have shown a role for melanocortin-5 receptors (MC5-R) in the stimulatory action of MCH, so we next investigated the involvement of both MCH1-R and/or MC5-R in mediating the actions of MCH on GnRH and hence LH release. The stimulatory action of MCH in the rPOA was inhibited by administration of antagonists for either MCH1-R or MC5-R. However, in the mPOA, the action of MCH was blocked only by the MC5-R antagonist. LH release was stimulated by an agonist for MC5-R injected into the rPOA or mPOA; this was blocked by the MC5-R antagonist but not the MCH1-R antagonist. These results indicate that both MCH1-R and MC5-R are involved in the central control of LH release by MCH. [source] APJ Receptor mRNA Expression in the Rat Hypothalamic Paraventricular Nucleus: Regulation By Stress and GlucocorticoidsJOURNAL OF NEUROENDOCRINOLOGY, Issue 11 2003A.-M. O'Carroll Abstract The apelin receptor (APJ receptor, APJR) has recently come to prominence following the isolation and identification of its endogenous ligand, apelin, from bovine stomach tissue extracts. Investigation of APJR mRNA expression has revealed a hypothalamic distribution similar to that of vasopressin suggesting that the apelin,APJR system may be involved in the regulation of the hypothalamic-adrenal-pituitary (HPA) stress axis. To investigate whether APJR is involved in the regulation of hypothalamic function during stress, APJR mRNA expression levels were measured by in situ hybridization in the hypothalamus of rats subjected to acute and repeated restraint stress. Acute stress caused an increase in APJR mRNA expression in the hypothalamic parvocellular paraventricular nucleus (pPVN) while repeated restraint stress induced a sustained up-regulation of pPVN APJR mRNA expression in intact rats. Removal of endogenous glucocorticoids by adrenalectomy also resulted in an increased expression of APJR mRNA in the PVN, suggesting a negative regulation of APJR mRNA expression by glucocorticoids. The role of glucocorticoids in mediating these stress-induced changes was investigated by analysing the effects of acute and repeated restraint stress on APJR mRNA levels in adrenalectomized rats. In these rats, APJR mRNA expression levels did not change above the already elevated levels of adrenalectomized-control rats. These data suggest that acute and repeated stress exert a stimulatory influence on APJR mRNA expression at the hypothalamic level that may be dependent on basal levels of circulating glucocorticoids, and further suggest a role for APJR in the regulation of hypothalamic function. [source] Systemic Administration of Ghrelin Induces Fos and Egr-1 Proteins in the Hypothalamic Arcuate Nucleus of Fasted and Fed RatsJOURNAL OF NEUROENDOCRINOLOGY, Issue 11 2000A. K. Hewson Abstract Ghrelin, a recently identified endogenous ligand for the growth hormone secretagogue (GHS) receptor, induces growth hormone (GH) secretion following systemic administration. We sought to determine whether systemic administration of ghrelin activates cells in the hypothalamic arcuate nucleus by examining the distribution of cells expressing Fos and Egr-1 proteins. In normally fed rats, both ghrelin and GHRP-6 (a synthetic GHS) significantly increased the number of cells expressing Fos and Egr-1 in the arcuate nucleus. The effects of ghrelin and GHRP-6 to induce Fos or Egr-1 protein expression was significantly greater in fasted than in fed rats. Thus, we show that (i) ghrelin is a centrally active peptide; (ii) it acts in a similar manner to synthetic GHS; and (iii) its central actions are increased in fasting, presumably reflecting physiological changes that accompany altered food intake and/or nutritional state. [source] Development of a potent and selective GPR7 (NPBW1) agonist: a systematic structure,activity study of neuropeptide BJOURNAL OF PEPTIDE SCIENCE, Issue 6 2007Maki Kanesaka Abstract Neuropeptide B (NPB) has been recently identified as an endogenous ligand for GPR7 (NPBW1) and GPR8 (NPBW2) and has been shown to possess a relatively high selectivity for GPR7. In order to identify useful experimental tools to address physiological roles of GPR7, we synthesized a series of NPB analogs based on modification of an unbrominated form of 23 amino acids with amidated C -terminal, Br(,)NPB-23-NH2. We confirmed that truncation of the N -terminal Trp residue resulted in almost complete loss of the binding affinity of NPB for GPR7 and GPR8, supporting the special importance of this residue for binding. Br(,)NPB-23-NH2 analogs in which each amino acid in positions 4, 5, 7, 8, 9, 10, 12 and 21 was replaced with alanine or glycine exhibited potent binding affinity comparable to the parent peptide. In contrast, replacement of Tyr11 with alanine reduced the binding affinity for both GPR7 and GPR8 four fold. Of particular interest, several NPB analogs in which the consecutive amino acids from Pro4 to Val13 were replaced with several units of 5-aminovaleric acid (Ava) linkers retained their potent affinity for GPR7. Furthermore, these Ava-substituted NPB analogs exhibited potent agonistic activities for GPR7 expressed in HEK293 cells. Among the Ava-substituted NPB analogs, analog 15 (Ava-5) and 17 (Ava-3) exhibited potency comparable to the parent peptide for GPR7 with significantly reduced activity for GPR8, resulting in high selectivity for GPR7. These highly potent and selective NPB analogs may be useful pharmacological tools to investigate the physiological and pharmacological roles of GPR7. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source] Alpha-retinals as Rhodopsin Chromophores,Preference for the 9- Z Configuration and Partial Agonist Activity,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2008Yajie Wang The visual pigment rhodopsin, the photosensory element of the rod photoreceptor cell in the vertebrate retina, shows in combination with an endogenous ligand, 11- Z retinal, an astonishing photochemical performance. It exhibits an unprecedented quantum yield (0.67) in a highly defined and ultrafast photoisomerization process. This triggers the conformational changes leading to the active state Meta(rhodopsin) II. Retinal is covalently bound to Lys-296 of the protein opsin in a protonated Schiff base. The resulting positive charge delocalization over the terminal part of the polyene chain of retinal creates a conjugation defect that upon photoexcitation moves to the opposite end of the polyene. Shortening the polyene as in 4,5-dehydro,5,6-dihydro (alpha), 5,6-dihydro or 7,8-dihydro-analogs might facilitate photoisomerization of a 9- Z and a 11- Z bond. Here we describe pigment analogs generated with bovine opsin and 11- Z or 9- Z 4,5-dehydro,5,6-dihydro-retinal that were further characterized by UV,Vis and FTIR spectroscopy. The preference of opsin for native 11- Z retinal over the 9- Z isomer is reversed in 4,5-dehydro,5,6-dihydro-retinal. 9- Z 4,5-dehydro,5,6-dihydro-retinal readily generated a photosensitive pigment. This modification has no effect on the quantum yield, but affects the Batho,blueshifted intermediate (BSI) equilibrium and leads to a strong decrease in the G-protein activation rate because of a downshift of the pKa of the Meta I,Meta II equilibrium. [source] Effect of food restriction on ghrelin in adult male rats and its relation to male reproductive hormonesANDROLOGIA, Issue 2 2010H. M. Abou Heif Summary Ghrelin is an endogenous ligand for growth hormone secretagogue (GHS) receptor (GHS-R). It has recently emerged as an orexigenic food intake controlling signal acting upon hypothalamic centres. To study the effect of food restriction on ghrelin level and its relation to male reproductive hormones, 32 adult male albino rats divided into two groups: Group I (8 rats as a control group) fed ad libitum for 21 days and 24 rats as Group II (food-restricted group) fed 30% of ad libitum intake of food consumed by the control group. Rats were weighed every 3 days. Group II rats were further subdivided into three subgroups: IIa, IIb and IIc that were killed at days 8, 16 and 21 from the start of food restriction respectively. Ghrelin level was assayed by ELISA technique in serum samples and tissue homogenates prepared from the stomach and hypothalamus. In addition, male reproductive hormones: testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were assayed in serum by chemiluminescence. Mean body weight of food restricted rats was observed to decrease during the period of the experiment. Food restriction produced a significant increase of serum ghrelin and a significant decrease of both gastric and hypothalamic ghrelin in group II when compared with group I. The changes in ghrelin level varied with the duration of food restriction. Significant inverse correlation was found between serum ghrelin and each of gastric and hypothalamic ghrelin in group II. A significant decrease of testosterone, FSH and LH were found in food restricted rats compared with controls. The decrease was significantly related to the duration of food restriction. Significant inverse correlation was detected between serum ghrelin and each of the male reproductive hormones in food restricted group II rats. Thus ghrelin could be one of the hormones responsible for the suppression of male reproductive axis in case of negative energy balance. [source] Nucleotide polymorphisms and the 5,-UTR transcriptional analysis of the bovine growth hormone secretagogue receptor 1a (GHSR1a) geneANIMAL SCIENCE JOURNAL, Issue 5 2010Masanori KOMATSU ABSTRACT Growth hormone secretagogue receptor 1a (GHSR1a) mediates the different actions of its endogenous ligand, ghrelin. Ghrelin-GHSR is involved in many important functions that include growth hormone secretion and food intake. We evaluated the haplotype variety and characterized the microsatellite ((TG)n, 5,-UTR) and nucleotide polymorphisms of the bovine GHSR1a gene. The nucleotide sequencing of this gene (,6 kb) revealed 47 single nucleotide polymorphisms (SNPs), four indels and the microsatellite ((GTTT)n, Intron 1). The 19 haplotypes were constructed from all nucleotide viability patterns and were divided into three major groups. Four SNPs (L24V, nt456(G>A), D191N and nt667(C>T)) and DelR242 in Exon 1 and a haplotype block of approximately 2.2 kb (nt667(C>T) , nt2884 (A>G)) were found in Bos taurus breeds. Breed differences in allele frequencies of the two microsatellites, nt-7(C>A), L24V, and DelR242 loci were found (P < 0.005). A DelR242 was found in the Japanese Shorthorn (frequency: , 0.44), Japanese Brown, five European cattle breeds, the Philippine native cattle, but none detected in the Japanese Black or the Mishima island cattle. Additionally, 5,-rapid amplification of cDNA ends and RT-PCR analyses revealed that there were two different kinds of transcripts: spliced, without a microsatellite within 5,-UTR (GHSR1a); and non-spliced, with the microsatellite (GHSR1b). [source] Expression of the endogenous, nicotinic acetylcholine receptor ligand, SLURP-1, in human colon cancerAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2008A. Pettersson Summary 1,Secreted mammalian Ly-6/urokinase plasminogen activator receptor-related protein-1 (SLURP-1) is a recently discovered endogenous ligand at the ,7 subunit of the nicotinic acetylcholine receptors. Previous reports have shown that SLURP-1 is expressed in normal human keratinocytes seemingly with a pro-apoptotic function. Conversely, such expression was markedly attenuated in transformed cells and it was suggested that the molecule could convey protection against malignant transformation. 2,In this study, we demonstrated the mRNA expression (by RT-PCR) and protein expression (by Western blotting and immunocytochemistry) of SLURP-1 in the human colon cancer cell line, HT-29. 3,Furthermore, we demonstrated the expression of SLURP-1 (by immunohistochemistry) in tumour cells of human colon cancer tissue, and, to a greater extent, in immune and smooth muscle cells of adjacent, macroscopically tumour-free colon tissue. 4,The current findings suggest that SLURP-1 participates in the regulation of gut immune functions and motility, as well as possibly playing a role in colon carcinogenesis/cancer progression. [source] Physiological roles of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligandBIOFACTORS, Issue 1 2009Takayuki Sugiura Abstract 2-Arachidonoylglycerol is an arachidonic acid-containing monoacylglycerol isolated from the rat brain and canine gut as an endogenous ligand for the cannabinoid receptors (CB1 and CB2). 2-Arachidonoylglycerol binds to both the CB1 receptor, abundantly expressed in the nervous system, and the CB2 receptor, mainly expressed in the immune system, with high affinity, and exhibits a variety of cannabimimetic activities. Notably, anandamide, another endogenous ligand for the cannabinoid receptors, acts as a partial agonist at these cannabinoid receptors, whereas 2-arachidonoylglycerol acts as a full agonist. The results of structure-activity relationship experiments strongly suggested that 2-arachidonoylglycerol rather than anandamide is the true natural ligand for both the CB1 and the CB2 receptors. Evidence is gradually accumulating which shows that 2-arachidonoylglycerol plays physiologically and pathophysiologically essential roles in various mammalian tissues and cells. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] Complete amino-acid sequence, crystallization and preliminary X-ray diffraction studies of leucurolysin-a, a nonhaemorrhagic metalloproteinase from Bothrops leucurus snake venomACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 8 2009Rodrigo Novaes Ferreira Leucurolysin-a (leuc-a) is a class P-I snake-venom metalloproteinase isolated from the venom of the South American snake Bothrops leucurus (white-tailed jararaca). The mature protein is composed of 202 amino-acid residues in a single polypeptide chain. It contains a blocked N-terminus and is not glycosylated. In vitro studies revealed that leuc-a dissolves clots made either from purified fibrinogen or from whole blood. Unlike some other venom fibrinolytic metalloproteinases, leuc-a has no haemorrhagic activity. Leuc-a was sequenced and was crystallized using the hanging-drop vapour-diffusion technique. Crystals were obtained using PEG 6000 or PEG 1500. Diffraction data to 1.80 and 1.60,Å resolution were collected from two crystals (free enzyme and the endogenous ligand,protein complex, respectively). They both belonged to space group P212121, with very similar unit-cell parameters (a = 44.0, b = 56.2, c = 76.3,Å for the free-enzyme crystal). [source] Neuropeptide S is a stimulatory anxiolytic agent: a behavioural study in miceBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008A Rizzi Background and purpose: Neuropeptide S (NPS) was recently identified as the endogenous ligand of an orphan receptor, now referred to as the NPS receptor. In vivo, NPS produces a unique behavioural profile by increasing wakefulness and exerting anxiolytic-like effects. In the present study, we further evaluated the effects of in vivo supraspinal NPS in mice. Experimental approach: Effects of NPS, injected intracerebroventricularly (i.c.v.), on locomotor activity (LA), righting reflex (RR) recovery and on anxiety states (measured with the elevated plus maze (EPM) and stress-induced hyperthermia (SIH) tests) were assessed in Swiss mice. Key results: NPS (0.01,1 nmol per mouse) caused a significant increase in LA in naive mice, in mice habituated to the test cages and in animals sedated with diazepam (5 mg kg,1). In the RR assay, NPS dose dependently reduced the proportion of animals losing the RR in response to diazepam (15 mg kg,1) and their sleeping time. In the EPM and SIH test, NPS dose dependently evoked anxiolytic-like effects by increasing the time spent by animals in the open arms and reducing the SIH response, respectively. Conclusions and implications: We provide further evidence that NPS acts as a novel modulator of arousal and anxiety-related behaviours by promoting a unique pattern of effects: stimulation associated with anxiolysis. Therefore, NPS receptor ligands may represent innovative drugs for the treatment of sleep and anxiety disorders. British Journal of Pharmacology (2008) 154, 471,479; doi:10.1038/bjp.2008.96; published online 31 March 2008 [source] Towards a Receptor for Nocistatin?BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2007E E Johnson Nocistatin is a peptide derived from the pronociceptin precursor, the source of nociceptin, the endogenous ligand for the nociceptin (NOP or ORL1). Despite nocistatin showing activity in a wide range of assays for nociception and other CNS activities, there is a dearth of information regarding the cellular actions of this peptide in the brain, and no receptor for nocistatin has been identified. In a study published in this issue of the British Journal of Pharmacology, Fantin and colleagues demonstrate that nocistatin inhibits 5-HT release from cortical synaptosomes in a concentration-dependent and Pertussis toxin-sensitive manner. The actions of nocistatin are independent of activity at NOP receptors. This study represents the first unambiguous demonstration of nocistatin agonist actions in brain and, taken together with previous work in the spinal cord, provides strong evidence that there is an as yet unidentified G protein-coupled receptor for nocistatin. British Journal of Pharmacology (2007) 152, 415,416; doi:10.1038/sj.bjp.0707384; published online 9 July 2007 [source] Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reactionBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2002Walter Raasch Since agmatine has been identified as a clonidine displacing substance (CDS), the aim of this study was to investigate whether agmatine can mimic CDS-induced cardiovascular reactions in organ bath experiments, pithed spontaneously hypertensive rats (SHR) and anaesthetized SHR. Intravenously-administered agmatine significantly reduced the blood pressure and heart rate of anaesthetized SHR at doses higher than 1 and 3 mg kg,1, respectively. These effects are probably mediated via central mechanisms, since there was an approximate 8 fold rightward shift of the dose-response curve in the pithed SHR (indicating a weakened cardiovascular effect). Moreover, in organ bath experiments, agmatine failed to alter the contractility of intact or endothelium-denuded aortal rings. When agmatine was administered i.c.v. to anaesthetized SHR, blood pressure was increased without any alteration of heart rate, whereas blood pressure was unchanged and heart rate was increased after injection into the 4th brain ventricle. This suggests that haemodynamic reaction patterns after central application are related to distinct influences on central cardiovascular mechanisms. Agmatine reduces noradrenaline release in pithed SHR while ,2 -adrenoceptors are irreversibly blocked with phenoxybenzamine, but not while I1 -binding sites are selectively blocked with AGN192403. This suggests that agmatine may modulate noradrenaline release in the same way that clonidine does, i.e. via imidazoline binding sites; this involves a reduction in sympathetic tone which in turn reduces blood pressure and heart rate. Finally, CDS-like cardiovascular activity appears not to be due to agmatine, since (i) blood pressure in anaesthetized SHR is decreased by agmatine and clonidine, and (ii) agmatine did not antagonize the blood pressure reaction to clonidine in pithed or anaesthetized SHR. British Journal of Pharmacology (2002) 135, 663,672; doi:10.1038/sj.bjp.0704513 [source] Stereoselective modulatory actions of oleamide on GABAA receptors and voltage-gated Na+ channels in vitro: a putative endogenous ligand for depressant drug sites in CNSBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2000Bernard Verdon cis -9,10-octadecenoamide (,oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. Twenty ,Mcis -oleamide (but not trans) reversibly enhanced GABAA currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. cis -oleamide stereoselectively blocked veratridine-induced (but not K+ -induced) depolarisation of mouse synaptoneurosomes (IC50, 13.9 ,M). The cis isomer stereoselectively blocked veratridine-induced (but not K+ -induced) [3H]-GABA release from mouse synaptosomes (IC50, 4.6 ,M). At 20 ,Mcis -oleamide, but not trans, produced a marked inhibition of Na+ channel-dependent rises in intrasynaptosomal Ca2+. The physiological significance of these observations was examined by isolating Na+ spikes in cultured pyramidal neurones. Sixty-four ,Mcis -oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). cis -Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC50 of 4.1 ,M suggesting a frequency- or state-dependent block of voltage-gated Na+ channels. Oleamide is a stereoselective modulator of both postsynaptic GABAA receptors and presynaptic or somatic voltage-gated Na+ channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal. British Journal of Pharmacology (2000) 129, 283,290; doi:10.1038/sj.bjp.0703051 [source] Structure,activity studies on high affinity NOP-active hexapeptidesCHEMICAL BIOLOGY & DRUG DESIGN, Issue 3 2004A.K. Judd Abstract:, Nociceptin/orphanin FQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the G-protein coupled receptor ORL1 (NOP), a member of the opioid receptor family. Although it is clear that this receptor system is involved in a variety of physiologic functions, including analgesia, the precise actions of N/OFQ remain largely uncharacterized. One reason for this has been limited number of high-affinity ligands to NOP, and particularly the lack of availability of useful specific antagonists. Herein, we describe the pharmacologic activity of a series of modified amino acid containing modifications of the hexapeptide Ac-RYYRWR-NH2, with high affinity for NOP. These compounds were tested for binding affinity using [3H]N/OFQ binding to human NOP in CHO cells, and functional activity by measuring stimulation of [35S]GTP,S-binding in CHO cell membranes. These studies suggest that each Arg of the hexapeptide is required to maintain high-binding affinity. The peptide maintains high affinity if the Tyr2 or Tyr3 are modified, but at least one of these residues must maintain its hydroxyl group or there is a large decrease in intrinsic activity of the peptide. [source] Angiotensin receptors in the eyes of arterial hypertensive ratsACTA OPHTHALMOLOGICA, Issue 4 2010Anu Vaajanen Abstract. Purpose:, The aim of the present study was to determine whether the eye tissues of arterial hypertensive rats evince expression of angiotensin receptors (AT1 and AT2) as well as the novel Mas receptor, whose endogenous ligand is vasorelaxing Angiotensin (1,7) [Ang (1,7)]. Methods:, Enucleated eyes from spontaneously hypertensive rats (SHR) and double transgenic rats harbouring human renin and angiotensinogen genes (dTGR) and their normotensive controls were used. Half of the rats were pretreated orally with an Angiotensin II (Ang II) type 1 receptor blocker (ARB). The eyes were snap-frozen in isopentane at ,40° and stored at ,70° for subsequent reverse transcriptase polymerase chain reaction (RT-PCR) analysis or in vitro autoradiography. Results:, The mRNA expression of AT1a and AT 2 as well as the novel Mas receptor was detected in all rat groups, being markedly higher in the retina than in the ciliary body. dTGR had significantly more receptors than SHR, but no direct relation to blood pressure level was seen. According to the autoradiography, treatment with ARB blocked a part of AT1 receptors but had no clear effect on AT2 receptors. Conclusion:, The novel Mas receptor was found by RT-PCR in eye tissue for the first time. Its specific ligand, Ang (1,7), may be involved in the regulation of intraocular pressure , as recently demonstrated by us , and in the pathogenesis of retinal diseases as a counter-regulatory component for the vascular and proliferative actions of Ang II. The results suggest that the density of AT1 receptors in the eye is independent of the blood pressure level of the animal. [source] Role of Toll-like receptor 4 in the initiation and progression of atherosclerotic diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2004G. Pasterkamp Abstract The family of Toll-like receptors (TLRs) initiates an innate immune response after recognition of pathogen-associated molecular patterns (PAMPs). Evidence is accumulating that TLRs, and particularly TLR4, are important players in the initiation and progression of atherosclerotic disease. Not only exogenous ligands but also endogenous ligands that are expressed during arterial injury are recognized by TLR4. Mouse knockout studies and epidemiological studies of human TLR4 polymorphisms have demonstrated that the TLR4 might play a role in the initiation and progression of atherosclerosis. This review will summarize the latest progression in research on the role of TLR4 in arterial occlusive disease In addition, the potential of intervention in TLR4 signalling to influence progression of atherosclerotic disease is discussed. [source] Pivotal role of Notch signaling in regulation of erythroid maturation and proliferationEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2006Yoshimichi Tachikawa Abstract:, Notch signaling plays an important role in cell fate decisions in developmental systems. To clarify its role in committed hematopoietic progenitor cells, we investigated the effects of Notch signaling in erythroid colony forming cells (ECFCs) generated from peripheral blood. ECFCs express Notch receptors, Notch1 and Notch2, and Notch ligands Delta1, Delta4, and Jagged1. When we assayed the effects of Notch ligands on erythroid maturation by flow cytometry, we found that immobilized Delta1 and immobilized Delta4 in particular inhibited maturation, whereas Jagged1 had no effect. In addition, Delta4 inhibited proliferation without reducing cell viability. Increases in expression levels of the Notch target gene hairy enhancer of split (HES) -1 were evident by real-time PCR after stimulation with immobilized Delta4. The effect of soluble Delta4 on expression of HES-1 was less pronounced than that seen with the immobilized form, indicating that all surface-bound ligands are important for effective signal transduction. When ECFCs were cultured in the presence of soluble Delta4 at a low cell concentration, erythroid maturation was slightly inhibited, but at a high concentration, maturation was promoted via competition of soluble Delta4 with endogenous ligands. These results indicate a pivotal role of Notch signaling in regulating erythroid maturation and proliferation, and further suggest that cell,cell interactions modulate growth of erythroid progenitor cells via Notch system. [source] Paucity of enkephalin production in neostriatal striosomal neurons: analysis with preproenkephalin,green fluorescent protein transgenic miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2008Yoshinori Koshimizu Abstract Whether or not the striosome compartment of the neostriatum contained preproenkephalin (PPE)-expressing neurons remained unresolved. To address this question by developing a sensitive detection method, we generated transgenic mice expressing enhanced green fluorescent protein (GFP) under the specific transcriptional control of the PPE gene. Eight transgenic lines were established, and three of them showed GFP expression which was distributed in agreement with the reported localization of PPE mRNA in the central nervous system. Furthermore, in the matrix compartment of the neostriatum of the three lines, intense GFP immunoreactivity was densely distributed in the neuronal cell bodies and neuropil, and matrix neurons displayed > 94% co-localization for GFP and PPE immunoreactivities. In sharp contrast, GFP immunoreactivity was very weak in the striosome compartment, which was characterized by intense immunoreactivity for mu-opioid receptors (MOR). Although neostriatal neurons were divided into GFP-immunopositive and -negative groups in both the striosome and matrix compartments, GFP immunoreactivity of cell bodies was much weaker (,1/5) in GFP-positive striosomal neurons than in GFP-positive matrix neurons. A similar reciprocal organization of PPE and MOR expression was also suggested in the ventral striatum, because GFP immunoreactivity was weaker in intensely MOR-immunopositive regions than in the surrounding MOR-negative regions. As PPE-derived peptides are endogenous ligands for MOR in the neostriatum and few axon collaterals of matrix neurons enter the striosome compartment, the present results raised the question of the target of those peptides produced abundantly by matrix neurons. [source] | |||||||||||||||||||||||||||||||||||||