Receptor最新文献

{"title":"Use of the mouse vas deferens to determine mu, delta, and kappa receptor affinities of opioid antagonists.","authors":"M L Cohen,&nbsp;L G Mendelsohn,&nbsp;C H Mitch,&nbsp;D M Zimmerman","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The present study was designed to identify a single smooth muscle preparation possessing mu, delta, and kappa receptors that can be used in the development of opioid selective antagonists. In vitro studies with the mouse vas deferens indicated that the delta selective agonists, DPLPE and DSLET, had potent agonist activity (ED50 approximately 1 nM) to inhibit the twitch response. The mu selective agonists, normorphine and fentanyl, also inhibited the twitch response in the mouse vas deferens, but were approx 100-fold less potent than the delta selective agonists, consistent with the enrichment of this preparation with delta receptors. U50,488, a kappa selective agonist, also inhibited the twitch response with a potency similar to that of the mu agonists. Naloxone, MR 2266, and WIN 44,441 all antagonized the agonist activity of U50,488 with antagonist dissociation constants distinct from those calculated using mu or delta receptor agonists. To confirm the presence of all three opioid receptors in this preparation, we examined a series of 14 phenylpiperidine opioid antagonists. An excellent correlation was observed between affinities of these piperidine opioid antagonists at mu and kappa receptors determined via radioligand binding studies, and affinities determined by blockade of fentanyl- or U50,488-induced twitch inhibition. Of the piperidine opioid antagonists studied, two possessed relatively high kappa receptor antagonist affinity. Furthermore, the study of an enantiomeric pair of an N-substituted 4-phenylpiperidine derivative demonstrated differences in absolute configuration to be more important for binding at mu and delta than kappa receptors. Thus, we have established the presence of kappa, in addition to the known mu and delta receptors, in the mouse vas deferens, and identified certain piperidines to have high kappa receptor antagonist affinity.</p>","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"4 1","pages":"43-53"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19032293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An exon encoding the mouse growth hormone binding protein (mGHBP) carboxy terminus is located between exon 7 and 8 of the mouse growth hormone receptor gene.","authors":"Y Zhou,&nbsp;L He,&nbsp;J J Kopchick","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A C57 black/6 mouse genomic library was screened for mGHR/BP using a mGHR cDNA hybridization probe. Two clones (mGHR-GA and mGHR-GB) were isolated. mGHR-GA contained an insert of 16 kb and hybridized only to exon 4 whereas mGHR-GB possessed an insert of 20 kb and hybridized to exons 6-10 of the mGHR cDNA. Oligonucleotide sequencing analysis confirmed that the mGHR-GA contained exon 4 and that the mGHR-GB possessed mGHR/BP genomic sequences from intron V through the 3' region of mGHR. In addition, mGHR-GB also contained a region, designated exon 8A, encoding the carboxy terminus of mGHBP. This exon is located between exons 7 and 8 of mGHR/BP gene. Two poly(A) additional signal sequences were found 54 bp downstream of the stop codon of mGHBP. Additionally, introns between exons 3/4 and 4/5 are > 12 and > 3 kb, respectively. Also, introns between exons 5/6, 6/7, 7/8A, 8A/8 (3' region of mGHBP), 8/9, 9/10, and the 3' region of mGHR are approx > 3 kb, 4 kb, 287 bp, 1569 bp, 6 kb, 265 bp, and > 3 kb, respectively. This study supports the hypothesis that mGHBP is generated by alternative splicing of a common primary mGHR transcript. It also demonstrates differences and similarities between mGHR/BP and hGHR genes.</p>","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"4 4","pages":"223-7"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18891468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of inducible cyclooxygenase (COX-2) in inflammation.","authors":"K Seibert,&nbsp;J L Masferrer","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Nonsteroidal anti-inflammatory drugs (NSAIDs) are potent anti-inflammatory agents that act through the inhibition of the cyclooxygenase (COX) enzyme and the subsequent inhibition of prostaglandins at the site of inflammation. Unfortunately, inhibition of gastrointestinal or renal prostaglandins is associated with mechanism-based toxicities that limit the usefulness of these otherwise potent and efficacious drugs. Recently two forms of the COX enzyme have been identified: COX-1, which is constitutively expressed in many cells and tissues, and COX-2, which is selectively induced by proinflammatory cytokines at the site of inflammation. The discovery of a second COX enzyme led to the hypothesis that toxicity associated with the clinically useful NSAIDs is caused by the inhibition of COX-1, whereas the anti-inflammatory properties were caused by the inhibition of inducible COX-2. In support of this hypothesis, expression of the inducible COX-2 enzyme is selectively blocked by the potent anti-inflammatory drug dexamethasone. Selective inhibition of COX-2 may produce superior anti-inflammatory drugs with substantial safety over existing NSAIDs.</p>","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"4 1","pages":"17-23"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19032289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dioxin-dependent, DNA sequence-specific binding of a multiprotein complex containing the Ah receptor.","authors":"C J Elferink,&nbsp;J P Whitlock","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Fractionation of rat liver cytosol, using as an affinity reagent the DNA recognition sequence for the liganded aromatic hydrocarbon (Ah) receptor, enriches for proteins that are about 110, 106, 98/96, 57, and 54 kDa in size. The proteins display 2,3,7,8-tetrachlorodibenzo-p-dioxin-dependent, DNA sequence-specific binding that is characteristic of the liganded Ah receptor. Immunological studies imply: 1. That the 98/96-kDa protein is the Ah receptor nuclear translocator (Arnt); 2. That the 110- and 106-kDa proteins are not immunologically related either to each other or to Arnt; and 3. That the 110-, the 106-kDa, and the Arnt proteins are members of a multicomponent protein complex. cDNA cloning studies indicate that the 106-kDa protein is the rat Ah receptor. The N-terminal 384 amino acids of the rat receptor show substantial sequence homology to the mouse and human Ah receptor. The sequence conservation across species imputes functional importance to this region of the receptor. In contrast, the remainder of the protein is substantially less well conserved among rat, mouse, and human. The tissue distribution of Ah receptor mRNA is consistent with previous studies of the distribution of the receptor protein. Our findings demonstrate the use of DNA recognition site chromatography for purification of the Ah receptor and imply that the ligand receptor binds to DNA as part of a multiprotein complex.</p>","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"4 3","pages":"157-73"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18812326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of human retinoic acid receptor alpha 1 expressed in recombinant baculovirus-infected Sf9 insect cells.","authors":"T C Quick,&nbsp;A M Traish,&nbsp;R M Niles","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Full-length human retinoic acid receptor alpha 1 (hRAR alpha 1) was expressed in Sf9 insect cells using the baculovirus expression vector system (BEVS). Western blot analysis using a specific anti-RAR peptide antiserum detected two major protein bands with apparent mol wts of approximately 54 and approximately 51 kDa in extracts from insect cells infected with recombinant hRAR alpha 1 Autographica californica (AcNPV) baculovirus. Analysis of recombinant extracts from Sf9 cells labeled in vivo with [32P]orthophosphate suggested that the recombinant protein was phosphorylated. A component in the recombinant nuclear extracts specifically bound [3H]all-trans-retinoic acid (RA) and sedimented in sucrose density gradient centrifugation as a single, symmetric peak with a sedimentation coefficient of approximately 3.6S, corresponding to a protein of approx 50 kDa. Scatchard analyses determined that [3H]RA was bound in recombinant extracts by a single class of binding sites with an apparent dissociation constant of approximately 0.3 nM and nuclear and cytoplasmic extracts contained approximately 1200 and approximately 200 pmoles, respectively, of unoccupied receptor per mg protein. In competitive ligand binding assays, relative binding affinities of 9-cis- and 13-cis-RA for hRAR alpha 1 in nuclear extracts were about threefold and sixfold lower than all-trans-RA, whereas all-trans-retinol, -retinaldehyde, and -retinyl acetate demonstrated relatively weak binding. In gel mobility shift assays, the electrophoretic migration of a [32P]-labeled oligonucleotide containing the retinoic acid response element of the RAR beta gene was retarded in the presence of recombinant nuclear and cytoplasmic extracts. The apparent complex formation between recombinant hRAR alpha 1 and beta RARE was greatly enhanced by the addition of nuclear extract from wild-type AcNPV-infected Sf9 cells, possibly because of heterodimer formation between recombinant hRAR alpha 1 and a metazoan RXR homolog. Thus, recombinant hRAR alpha 1 expressed at high levels in Sf9 insect cells exhibited biochemical properties of the native protein, including nuclear translocation, specific high affinity ligand and RARE binding, and possible heterodimer formation.</p>","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"4 2","pages":"65-80"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18946889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interleukin-1 receptor antagonist and its delivery by gene transfer.","authors":"C H Evans,&nbsp;P D Robbins","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The interleukin-1 receptor antagonist (IL-1ra or IRAP) is a small, acidic glycoprotein that competitively inhibits the biological activities of interleukin-1 (IL-1). Alternative splicing gives rise to secreted and intracellular forms of IL-1ra. Both forms block cellular responses to IL-1 by occupying IL-1 receptors without triggering an agonist response. The affinity of IL-1ra for the type I IL-1 receptor is approximately that of IL-1. However, because of IL-1's pronounced \"spare receptor\" effect, IL-1ra is a weak inhibitor of biological responses to IL-1. The value for the affinity constant of IL-1ra's binding to the type II IL-1 receptor has been the subject of disagreement. However, recent data suggest that human IL-1ra has only weak affinity for the human type II receptor. This is consistent with the likelihood that the type II receptor plays no role in signal transduction, instead being a \"decoy\" that can be shed as a soluble receptor with the ability bind, and thus inhibit, IL-1. Under the name Antril, IL-1ra is being tested in clinical trials of a number of human diseases where IL-1 plays a major pathophysiologic role. These diseases include sepsis, rheumatoid arthritis, chronic myelogenous leukemia, and asthma, among others. Although IL-1ra has clear pharmacologic potential in such conditions, its application in chronic diseases is limited by difficulties associated with delivering proteins as drugs. As an alternative, we have suggested transfer of the gene coding for IL-1ra; strategies for both local and systemic gene delivery are being developed.(ABSTRACT TRUNCATED AT 250 WORDS)</p>","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"4 1","pages":"9-15"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19032830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in triiodothyronine (T3) mononuclear leukocyte receptor kinetics after T3 administration and multiple cold-air exposures.","authors":"M M D'Alesandro,&nbsp;M Malik,&nbsp;H L Reed,&nbsp;L D Homer","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Repeated cold-air exposures increase human triiodothyronine (T3) plasma clearance rates. To study the response of the nuclear T3 receptor (NT3R) in this condition, binding characteristics were analyzed in human mononuclear leukocytes (MNL). In addition, we supplemented one group of individuals with a daily oral replacement dose of T3 to isolate the influence of serum thyroxine (T4) and thyrotropin (TSH) levels on receptor kinetics. The subjects were exposed to cold air (4 degrees C) twice/d, 30 min/exposure, for a total of 80 exposures. The T3-subjects received placebo [n = 8] and the T3 + subjects received T3 (30 micrograms/d) [n = 8] in a double-blind fashion. Mononuclear leukocytes were isolated from peripheral blood before the cold exposure and drug regimen began, and then after every 20 exposures. The dissociation constant (Kd) and maximum binding capacity (MBC) of the NT3R values were log transformed to minimize between-subject variability. In the T3+ group, serum total thyroxine (TT4), free T4 (FT4), and TSH were approx 50% lower than both basal and T3-values. The log10Kd increased 0.304 +/- 0.139 (p < 0.04) and the log10MBC increased 0.49 +/- 0.10 (p < 0.001) in the T3+ subjects compared to baseline. This change in MBC represents a 311% increase in the MBC over baseline and a fivefold increase over placebo-treated subjects. The T3- group showed no change in MBC over the study. These results describe for the first time the rapid modulation of the NT3R in response to the combined influence of cold exposure and reduced circulating T4 and TSH.</p>","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"4 4","pages":"259-68"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18890759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hormone receptors and the regulation of insect metamorphosis.","authors":"L. Riddiford, J. Truman","doi":"10.1093/ICB/33.3.340","DOIUrl":"https://doi.org/10.1093/ICB/33.3.340","url":null,"abstract":"Presented is a brief review of the role of ecdysteroid and juvenile hormone (JH) receptors in the regulation of insect larval molting and metamorphosis of the epidermis and the nervous system, using examples from Manduca sexta and Drosophila melanogaster. Ecdysteroids cause a molt by combining with the ecdysone receptor (EcR) and the ultraspiracle protein (both members of the steroid hormone receptor superfamily) to activate directly a number of regulatory genes whose products both repress ongoing gene expression and stimulate genes associated with the production of the new stage in a cascading fashion. The presence of the JH-JH receptor (JHR) ensures that the molt is to another larval stage. At metamorphosis in the absence of JH, a new isoform of EcR and some new ecdysteroid-induced regulatory factors appear in response to low ecdysteroid. The subsequent high ecdysteroid then can activate a new cascade, causing the pupal molt. Also, the quantity of the new EcR isoform in metamorphosing larval neurons during adult development is correlated with cell fate. The JHR found in larval tissues is a 29-kDa nuclear protein that specifically binds JH with high affinity and is dependent on the presence of JH during ecdysteroid rises for its continued synthesis. This JHR represents a new class of intranuclear hormone receptors since it has no known DNA-binding domains and has a discrete subnuclear localization different from that of the EcR. Its specific action is unknown.","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"11 1","pages":"203-9"},"PeriodicalIF":0.0,"publicationDate":"1993-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81670934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a specific pattern of \"immediate-early\" gene activation induced by estrogen during mitogenic stimulation of rat uterine cells.","authors":"L Cicatiello,&nbsp;V Sica,&nbsp;F Bresciani,&nbsp;A Weisz","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Estrogen hormones are potent mitogens for certain target tissues, where they stimulate cell growth by inducing recruitment of quiescent cells in cycle and by fostering cell cycle progression. To define the molecular bases of the mitogenic action of these steroid hormones, the pattern of \"immediate-early\" gene expression was monitored during the early phases of estrogen stimulation of rat uterine cells in vivo. Nuclear run-on transcription and/or Northern blot RNA analysis indicate that c-jun, junB, jun-D, c-fos, TIS 1 (also called NGFI-B or nur/77) and TIS 8 (zif-268, krox24, egr-1, or NGFI-A) genes are all transiently activated in the uterus (up to 20-fold) within 30-120 min after treatment of adult ovariectomized rats with a mitogenic dose of 17b-estradiol. Conversely, JE gene mRNA accumulates progressively in estrogen-stimulated uterine cells, whereas TIS 11 and 21 genes are only slightly responsive to the hormone (less than twofold induction) and fos B,fra-1,fra-2,krox20 (egr-2), TIS 7 and 10, KC, and c-rel mRNAs are undetectable in rat uterus either before or after estrogen treatment. Stimulation in the presence of cycloheximide shows that only c-jun, jun-D, c-fos, and JE gene activations are primary responses to the hormone in rat uterine cells. These findings establish the direct mitogenic role of estrogen and identify for the first time a specific genetic program activated by these steroid hormones during stimulation of target cell proliferation. Furthermore, since most of the activated genes encode for transcription factors, these results enable us to envision how the mitogenic signal transmitted by the hormone can be elaborated and amplified within target cells by the products of estrogen-responsive genes, leading to a cascade of growth-dependent gene regulation, cell cycle progression, and, ultimately, cell division.</p>","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"3 1","pages":"17-30"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19334595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear protein kinase C and signal transduction.","authors":"A N Malviya,&nbsp;C Block","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Protein kinase C (pKC) is a family of enzymes, consisting of ten isoenzymes. Some of the members of the pKC family are not dependent on calcium for their activity and also do not bind diacylglycerol. Protein kinase C is either translocated to the nucleus or present endogenously. Both calcium-dependent as well as calcium-independent isoenzymes are located in the nucleus. Protein kinase C has specific functions in the events activated within the nucleus during signal transduction. Three lines of approach have been taken to discern the nuclear function of pKC: pathways of activation of cytosolic pKC regulating nuclear events; translocation of pKC to the nucleus from the cytosol, and activation of native pKC in isolated nuclei. Protein kinase C contains a nuclear targeting bipartite motif and has a role in the nuclear calcium signaling process. Targeting and binding of pKC to the sites of replicational and posttranscriptional activity may be one of the mechanisms of the pKC signaling process. Protein kinase C-mediated activation of nuclear phosphatases and dephosphorylation of target nuclear proteins are the areas where much less attention has been paid. Exploring these avenues may lead to new insights into the molecular mechanism of nuclear signal transduction.</p>","PeriodicalId":21112,"journal":{"name":"Receptor","volume":"3 4","pages":"257-75"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19135712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}