Somatostatin Receptor Subtype Expression in the Human Heart: Differential Expression by Myocytes and fibroblasts

Total Page:16

File Type:pdf, Size:1020Kb

Somatostatin Receptor Subtype Expression in the Human Heart: Differential Expression by Myocytes and fibroblasts 379 Somatostatin receptor subtype expression in the human heart: differential expression by myocytes and fibroblasts William H T Smith, R Unnikrishnan Nair1, Dawn Adamson2, Mark T Kearney3, Stephen G Ball and Anthony J Balmforth Integrated Molecular Cardiology Group, University of Leeds, Leeds LS2 9JT, UK 1Department of Cardiothoracic Surgery, The General Infirmary at Leeds, Leeds LS1 3EX, UK 2National Heart and Lung Institute, Imperial College, London SW3 6LY, UK 3GKT School of Medicine, London WC2R 2LS, UK (Requests for offprints should be addressed to A J Balmforth; Email: [email protected]) Abstract In acromegaly, somatostatin receptor ligands (SRLs) can and sst5) were shown to be co-expressed by the human ameliorate left ventricular hypertrophy (LVH) and their heart. These receptors were present in both atrial and use is associated with demonstrable improvements in ventricular tissue. Human cardiac myocytes expressed various parameters of cardiac function. It remains unclear mRNA for only sst1 and sst2, while human cardiac as to whether these beneficial effects are principally fibroblasts expressed all four subtypes found in whole heart attributable to falling GH and IGF-I levels, or whether tissue. The expression of functional somatostatin receptors SRLs exert independent direct effects on the heart via on human cardiac fibroblasts was confirmed by mobilis- somatostatin receptors. To help address this issue, we have ation of intracellular calcium in response to somatostatin. sought to investigate somatostatin receptor expression The presence of cardiac somatostatin receptors raises the in human heart. A human heart cDNA library was possibility of a direct effect of somatostatin analogues on probed using PCR techniques to determine expression of the heart. Furthermore, the differential expression of somatostatin receptor subtypes. Subsequently, human somatostatin receptor subtypes by human cardiac myo- heart biopsies and human cardiac fibroblasts and myocytes cytes and fibroblasts opens up the possibility of differ- were analysed to determine whether expression differed ential modulation of the cell types in the heart by between cardiac chambers or cell types. mRNAs for four subtype-specific somatostatin analogues. of the five somatostatin receptor subtypes (sst1, sst2, sst4 Journal of Endocrinology (2005) 187, 379–386 Introduction complications of cardiac involvement in acromegaly (Clayton 2003). The coexistence of hypertension increases Acromegaly is a rare but important endocrine disorder the incidence of cardiac abnormalities (Colao et al. 2000a) associated with a reduced life expectancy. Subjects with and the risk of premature death (Holdaway et al. 2004). uncontrolled acromegaly have a 2- to 5-fold greater Treatment with the somatostatin receptor ligands mortality than controls, 60% of which is due to cardio- (SRLs) octreotide (Lim et al. 1992, Tokgozoglu et al. vascular disease (Wright et al. 1970, Orme et al. 1998). 1994, Colao et al. 2000b) and lanreotide (Baldelli et al. The main structural cardiac abnormality is left ventricular 1999, Manelli et al. 1999) has been shown to promote hypertrophy (LVH) (for review see Colao et al. (2001a)). regression of LVH with some studies also demonstrating LVH in acromegaly is characterised by both myo- improvements in left ventricular diastolic function cyte hypertrophy and a disproportionate accumulation of (Thuesen et al. 1989, Merola et al. 1993, Colao et al. fibrillar collagen (up to 8-fold greater than in biopsies 1999). It is worth noting, however, that while these results from patients with mitral stenosis (Frustaci et al. 1999). are encouraging, to date, no studies have been of sufficient Lymphomononuclear infiltration and areas of monocyte duration to establish whether normalising cardiac struc- necrosis resembling myocarditis have also been described ture ultimately translates into reduced cardiovascular mor- (Lie 1980). These changes are likely to account for the tality. In the meantime, therefore, we are dependent upon observed functional abnormalities of impaired left ven- demonstrating improvements in surrogate markers of tricular diastolic function, impaired exercise tolerance disease activity while the results of long-term follow-up and ventricular arrhythmias which are recognised studies are awaited. In this regard, treatment with SRLs is Journal of Endocrinology (2005) 187, 379–386 DOI: 10.1677/joe.1.06082 0022–0795/05/0187–379 2005 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/28/2021 03:42:02PM via free access 380 W H T SMITH and others · Somatostatin receptor subtype expression in human heart effective in suppressing various markers of acromegalic Table 1 PCR primers used in reactions to detect somatostatin disease activity (Ezzat et al. 1992), which in turn has been receptor subtypes (5–3) associated with improved overall survival (Orme et al. 1998, Holdaway et al. 2004). Furthermore, improvements sst1 FP CGCTGGCTGGTGGGCTTCGTGTTG in exercise capacity (Padayatty et al. 1996) and cardiac sst1 RP CGCCGCCGGACTCCAGGTTCTCAG output in subjects with heart failure (Chanson et al. sst2 FP TCCAGGGTCCATTAAGGTGAGAA 1990) have been reported following octreotide therapy. sst2 RP TAGGGAGCCCATTGCCAGTAGAC Together these data have led some authors to suggest that sst3 FP CGTGGTGGGCCTGCTGGGTAACTC restoring cardiac structure and function should become an sst3 RP GTGCGGCCGTGTAGATGATGAAGC sst4 FP GTGTGGCTGGCATCCCTGTTGGTC objective of treatment in acromegaly (Clayton 2003). sst4 RP GATCGGCGGAAGTTGTCGGAGAGG Up until now it has generally been assumed that LVH sst5 FP TACATGCTGGGGCTGCCTTTCCTG regression in response to SRL therapy is mediated through sst5 RP GCCCGCCGCCCTCACCTTCAC the reduction in circulating growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels (Colao et al. FP, forward primer; RP, reverse primer. 2001b). To our knowledge, no studies have so far sought to determine whether there is a direct cardiac effect of SRLs in the reversal of acromegaly-associated cardio- myopathy and its consequences. Morover, if such an effect for studies in human tissue if meaningful conclusions with was present, it would mandate further studies to explore direct relevance to clinical practice are to be drawn. its potential relevance in patients with pathological LVH In this study we have determined somatostatin receptor subtype expression at the mRNA level in the human of other causes such as hypertension. ff LVH is a frequent complication of hypertension with its heart. We have identified di erential receptor subtype presence well recognised as a marker for risk of death expression between myocytes and fibroblasts and demon- (Levy et al. 1994). Previously reported data suggest that strate mobilisation of intracellular calcium in response to regression of LVH associated with antihypertensive somatostatin in human cardiac fibroblasts. therapy is associated with improved outcome (Verdecchia et al. 1998, Mathew et al. 2001). The pathological changes in hypertensive LVH are similar to those found in acrome- Materials and Methods galy with disproportionate proliferation of cardiac fibro- blasts and accumulation of fibrillar collagen. This growth PCR analysis used to identify expression of human of the cardiac interstitium has significant functional effects somatostatin receptor subtypes on the left ventricle leading to abnormal relaxation and the The primer pairs used for PCR analysis are shown in Table clinical syndrome of heart failure even before the develop- 1. Optimal PCR conditions for amplification of all five ment of systolic dysfunction (Weber & Brilla 1991). receptor subtypes were established using a QUICK Screen Modulation of cardiac fibroblasts is therefore of particular universal human cDNA library (Clontech) as a template. interest in both acromegaly and hypertension. Several For sst1, sst3, sst4 and sst5 receptors, a GC-2 cDNA PCR factors have been shown to contribute to the development kit (Clontech) was used. Each 50 µl reaction consisted of: ff of LVH in hypertension but particular interest has focused 24 µl ultrapure H2O, 10 µl 5 bu er, 10 µl GC Melt, on IGF-I (for review see Delafontaine (1995)). 1µl50 dNTP mix (10 mM), 1 µl forward primer The peptide hormone somatostatin can inhibit both the (25 µM), 1 µl reverse primer (25 µM), 1 µl Advantage GC release and mitogenic effects of growth factors including Polymerase Mix, 2 µl template cDNA. Cycle parameters IGF-I. It exerts its effects through five G-protein-coupled used were: 94 C for 60 s (activation) followed by 35 cycles receptor subtypes (sst1–sst5). These receptors couple to a of 94 C for 30 s (melting) and 68 C for 180 s (combined variety of signal transduction pathways –including inhibi- annealing extension). This was followed by a final exten- tion of adenylate cyclase (Patel et al. 1994), mobilisation of sion period of 180 s at 68 C. For sst2 receptors, an intracellular calcium (Akbar et al. 1994) and activation of Advantage PCR kit (Clontech) was used. Each 50 µl protein tyrosine phosphatases (Buscail et al. 1995) – which reaction consisted of: 40 µl ultrapure H20, 5 µl 10 can inhibit cell proliferation. In rat heart, sst1, sst3 and sst4 cDNA PCR buffer, 1 µl 50 dNTP mix (10 mM), 1 µl are expressed but sst2 and sst5 are not, as evidenced by forward primer (25 µM), 1 µl reverse primer (25 µM), 1 µl mRNA expression (Bruno et al. 1993). In the human heart, Advantage Polymerase Mix, 1 µl template cDNA. Cycle mRNA encoding
Recommended publications
  • Coexpression of Human Somatostatin Receptor-2 (SSTR2) and SSTR3 Modulates Antiproliferative Signaling and Apoptosis Sajad a War and Ujendra Kumar*
    War and Kumar Journal of Molecular Signaling 2012, 7:5 http://www.thrombosisjournal.com/7/1/5 RESEARCH ARTICLE Open Access Coexpression of human somatostatin receptor-2 (SSTR2) and SSTR3 modulates antiproliferative signaling and apoptosis Sajad A War and Ujendra Kumar* Abstract Background: Somatostatin (SST) via five Gi coupled receptors namely SSTR1-5 is known to inhibit cell proliferation by cytostatic and cytotoxic mechanisms. Heterodimerization plays a crucial role in modulating the signal transduction pathways of SSTR subtypes. In the present study, we investigated human SSTR2/SSTR3 heterodimerization, internalization, MAPK signaling, cell proliferation and apoptosis in HEK-293 cells in response to SST and specific agonists for SSTR2 and SSTR3. Results: Although in basal conditions, SSTR2 and SSTR3 colocalize at the plasma membrane and exhibit heterodimerization, the cell surface distribution of both receptors decreased upon agonist activation and was accompanied by a parallel increase in intracellular colocalization. Receptors activation by SST and specific agonists significantly decreased cAMP levels in cotransfected cells in comparison to control. Agonist-mediated modulation of pERK1/2 was time and concentration-dependent, and pronounced in serum-deprived conditions. pERK1/2 was inhibited in response to SST; conversely receptor-specific agonist treatment caused inhibition at lower concentration and activation at higher concentration. Strikingly, ERK1/2 phosphorylation was sustained upon prolonged treatment with SST but not with receptor-specific agonists. On the other hand, SST and receptor-specific agonists modulated p38 phosphorylation time-dependently. The receptor activation in cotransfected cells exhibits Gi-dependent inhibition of cell proliferation attributed to increased PARP-1 expression and TUNEL staining, whereas induction of p21 and p27Kip1 suggests a cytostatic effect.
    [Show full text]
  • PDF (Appendices)
    Appendix I: Upregulated genes in OGT cKO hippocampi at 2 months of age Gene Symbol Description log2 FC Ccl3 chemokine (C-C motif) ligand 3 5.0 Clec7a C-type lectin domain family 7, member a 4.9 Cst7 cystatin F (leukocystatin) 4.9 Cxcl10 chemokine (C-X-C motif) ligand 10 4.3 Ccl4 chemokine (C-C motif) ligand 4 3.9 Itgax integrin alpha X 3.6 Isg15 ISG15 ubiquitin-like modifier 3.2 Ccl12 chemokine (C-C motif) ligand 12|c-C motif chemokine 12-like 3.2 Glycam1 glycosylation dependent cell adhesion molecule 1 3.1 Ccl5 chemokine (C-C motif) ligand 5 3.0 Usp18 ubiquitin specific peptidase 18 3.0 Ifi27l2a interferon, alpha-inducible protein 27 like 2A 2.9 Ccl6 chemokine (C-C motif) ligand 6 2.9 Cd52 CD52 antigen 2.9 Taar3 trace amine-associated receptor 3 2.8 Ifit1 interferon-induced protein with tetratricopeptide repeats 1 2.7 Irf7 interferon regulatory factor 7 2.7 Timp1 tissue inhibitor of metalloproteinase 1 2.7 Pyhin1 pyrin and HIN domain family, member 1 2.7 Zc3h12d zinc finger CCCH type containing 12D 2.7 Gfap glial fibrillary acidic protein 2.6 Trem2 triggering receptor expressed on myeloid cells 2 2.6 Rtp4 receptor transporter protein 4 2.5 Cxcl9 chemokine (C-X-C motif) ligand 9 2.5 C3ar1 complement component 3a receptor 1 2.5 I830012O16Rik RIKEN cDNA I830012O16 gene 2.5 Mpeg1 macrophage expressed gene 1 2.4 Lag3 lymphocyte-activation gene 3 2.3 Lgals3bp lectin, galactoside-binding, soluble, 3 binding protein 2.3 Bst2 bone marrow stromal cell antigen 2 2.3 Slc15a3 solute carrier family 15, member 3 2.3 Siglec5 sialic acid binding Ig-like lectin 5 2.3 Endou endonuclease, polyU-specific 2.2 Oasl2 2'-5' oligoadenylate synthetase-like 2 2.2 Ch25h cholesterol 25-hydroxylase 2.2 Aspg asparaginase homolog (S.
    [Show full text]
  • Arborization of Dendrites by Developing Neocortical Neurons Is Dependent on Primary Cilia and Type 3 Adenylyl Cyclase
    2626 • The Journal of Neuroscience, February 6, 2013 • 33(6):2626–2638 Development/Plasticity/Repair Arborization of Dendrites by Developing Neocortical Neurons Is Dependent on Primary Cilia and Type 3 Adenylyl Cyclase Sarah M. Guadiana,1 Susan Semple-Rowland,1 Daniel Daroszewski,1 Irina Madorsky,1 Joshua J. Breunig,2 Kirk Mykytyn,3 and Matthew R. Sarkisian1 1Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0244, 2Cedars-Sinai Regenerative Medicine Institute, Los Angeles, California 90036, and 3Department of Pharmacology, Wexner Medical Center, Ohio State University, Columbus, Ohio 43210 The formation of primary cilia is a highly choreographed process that can be disrupted in developing neurons by overexpressing neuromodulatory G-protein-coupled receptors GPCRs or by blocking intraflagellar transport. Here, we examined the effects of overex- pressing the ciliary GPCRs, 5HT6 and SSTR3, on cilia structure and the differentiation of neocortical neurons. Neuronal overexpression of 5HT6 and SSTR3 was achieved by electroporating mouse embryo cortex in utero with vectors encoding these receptors. We found that overexpression of ciliary GPCRs in cortical neurons, especially 5HT6, induced the formation of long (Ͼ30 ␮m) and often forked cilia. These changes were associated with increased levels of intraflagellar transport proteins and accelerated ciliogenesis in neonatal neocor- tex, the induction of which required Kif3a, an anterograde motor critical for cilia protein trafficking and growth. GPCR overexpression also altered the complement of signaling molecules within the cilia. We found that SSTR3 and type III adenylyl cyclase (ACIII), proteins normally enriched in neuronal cilia, were rarely detected in 5HT6-elongated cilia. Intriguingly, the changes in cilia structure were accompanied by changes in neuronal morphology.
    [Show full text]
  • Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Amy Sue Bogard University of Tennessee Health Science Center
    University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2013 Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Amy Sue Bogard University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Medical Cell Biology Commons, and the Medical Molecular Biology Commons Recommended Citation Bogard, Amy Sue , "Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells" (2013). Theses and Dissertations (ETD). Paper 330. http://dx.doi.org/10.21007/etd.cghs.2013.0029. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Biomedical Sciences Track Molecular Therapeutics and Cell Signaling Research Advisor Rennolds Ostrom, Ph.D. Committee Elizabeth Fitzpatrick, Ph.D. Edwards Park, Ph.D. Steven Tavalin, Ph.D. Christopher Waters, Ph.D. DOI 10.21007/etd.cghs.2013.0029 Comments Six month embargo expired June 2014 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/330 Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Amy Sue Bogard December 2013 Copyright © 2013 by Amy Sue Bogard.
    [Show full text]
  • Oxygenated Fatty Acids Enhance Hematopoiesis Via the Receptor GPR132
    Oxygenated Fatty Acids Enhance Hematopoiesis via the Receptor GPR132 The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Lahvic, Jamie L. 2017. Oxygenated Fatty Acids Enhance Hematopoiesis via the Receptor GPR132. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061504 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Oxygenated Fatty Acids Enhance Hematopoiesis via the Receptor GPR132 A dissertation presented by Jamie L. Lahvic to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Developmental and Regenerative Biology Harvard University Cambridge, Massachusetts May 2017 © 2017 Jamie L. Lahvic All rights reserved. Dissertation Advisor: Leonard I. Zon Jamie L. Lahvic Oxygenated Fatty Acids Enhance Hematopoiesis via the Receptor GPR132 Abstract After their specification in early development, hematopoietic stem cells (HSCs) maintain the entire blood system throughout adulthood as well as upon transplantation. The processes of HSC specification, renewal, and homing to the niche are regulated by protein, as well as lipid signaling molecules. A screen for chemical enhancers of marrow transplant in the zebrafish identified the endogenous lipid signaling molecule 11,12-epoxyeicosatrienoic acid (11,12-EET). EET has vasodilatory properties, but had no previously described function on HSCs.
    [Show full text]
  • Dynamic Mass Redistribution Reveals Diverging Importance of PDZ
    Pharmacological Research 105 (2016) 13–21 Contents lists available at ScienceDirect Pharmacological Research j ournal homepage: www.elsevier.com/locate/yphrs Dynamic mass redistribution reveals diverging importance of PDZ-ligands for G protein-coupled receptor pharmacodynamics a b b b Nathan D. Camp , Kyung-Soon Lee , Allison Cherry , Jennifer L. Wacker-Mhyre , b b b b Timothy S. Kountz , Ji-Min Park , Dorathy-Ann Harris , Marianne Estrada , b b a b,∗ Aaron Stewart , Nephi Stella , Alejandro Wolf-Yadlin , Chris Hague a Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA b Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195, USA a r t i c l e i n f o a b s t r a c t Article history: G protein-coupled receptors (GPCRs) are essential membrane proteins that facilitate cell-to-cell Received 19 October 2015 communication and co-ordinate physiological processes. At least 30 human GPCRs contain a Type I PSD- Received in revised form 95/DLG/Zo-1 (PDZ) ligand in their distal C-terminal domain; this four amino acid motif of X-[S/T]-X-[␸] 28 December 2015 sequence facilitates interactions with PDZ domain-containing proteins. Because PDZ protein interactions Accepted 1 January 2016 have profound effects on GPCR ligand pharmacology, cellular localization, signal-transduction effector Available online 7 January 2016 coupling and duration of activity, we analyzed the importance of Type I PDZ ligands for the function of 23 full-length and PDZ-ligand truncated (PDZ) human GPCRs in cultured human cells. SNAP-epitope tag Keywords: polyacrylamide gel electrophoresis revealed most Type I PDZ GPCRs exist as both monomers and mul- G protein-coupled receptor timers; removal of the PDZ ligand played minimal role in multimer formation.
    [Show full text]
  • Probing Cell Type–Specific Functions of Gi in Vivo Identifies GPCR Regulators of Insulin Secretion
    Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion Jean B. Regard, … , Matthias Hebrok, Shaun R. Coughlin J Clin Invest. 2007;117(12):4034-4043. https://doi.org/10.1172/JCI32994. Research Article Technical Advance Cardiology The in vivo roles of the hundreds of mammalian G protein–coupled receptors (GPCRs) are incompletely understood. To explore these roles, we generated mice expressing the S1 subunit of pertussis toxin, a known inhibitor of Gi/o signaling, under the control of the ROSA26 locus in a Cre recombinase–dependent manner (ROSA26PTX). Crossing ROSA26PTX mice to mice expressing Cre in pancreatic β cells produced offspring with constitutive hyperinsulinemia, increased insulin secretion in response to glucose, and resistance to diet-induced hyperglycemia. This phenotype underscored the known importance of Gi/o and hence of GPCRs for regulating insulin secretion. Accordingly, we quantified mRNA for each of the approximately 373 nonodorant GPCRs in mouse to identify receptors highly expressed in islets and examined the role of several. We report that 3-iodothyronamine, a thyroid hormone metabolite, could negatively and positively regulate insulin secretion via the Gi-coupled α2A-adrenergic receptor and the Gs-coupled receptor Taar1, respectively, and protease- activated receptor–2 could negatively regulate insulin secretion and may contribute to physiological regulation of glucose metabolism. The ROSA26PTX system used in this study represents a new genetic tool to achieve tissue-specific signaling pathway modulation in vivo that can be applied to investigate the role of Gi/o-coupled GPCRs in multiple cell types and processes. Find the latest version: https://jci.me/32994/pdf Technical advance Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion Jean B.
    [Show full text]
  • 763.Full.Pdf
    1521-0081/70/4/763–835$35.00 https://doi.org/10.1124/pr.117.015388 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:763–835, October 2018 Copyright © 2018 The Author(s). This is an open access article distributed under the CC BY Attribution 4.0 International license. ASSOCIATE EDITOR: ELIOT H. OHLSTEIN International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature Thomas Günther, Giovanni Tulipano, Pascal Dournaud, Corinne Bousquet, Zsolt Csaba, Hans-Jürgen Kreienkamp, Amelie Lupp, Márta Korbonits, Justo P. Castaño, Hans-Jürgen Wester, Michael Culler,1 Shlomo Melmed, and Stefan Schulz Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P. C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.) Downloaded from Abstract ...................................................................................765 I.
    [Show full text]
  • Onadotropin-Releasing Hormone Receptor CLAVULANIC ACID
    ARGININE DAPAGLIFLOZIN ORVEPITANT ORLISTAT Nitric oxideNitric-oxide synthase- synthase- inducible brain Sodium/glucose cotransporter 1 Substance-P receptor Gastric triacylglycerolSodium/glucose lipase cotransporter 2 Platelet activating factor receptor Cystic fibrosis transmembrane conductance regulator Pancreatic lipase-related protein 2 Pancreatic triacylglycerol lipase IVACAFTOR LUMACAFTORDENUFOSOL TETRASODIUM Pyrimidinergic receptor P2Y6 GABA receptorPENTOBARBITAL beta-3 subunit TEZOSENTAN Geranylgeranyl transferase type I Endothelin receptor ET-A TIPIFARNIB Leukocyte commonCholecystokinin antigen B receptor PurinergicPyrimidinergic receptor receptor P2Y2 P2Y4 TALNETANT DARUSENTANIRBESARTAN ETOPOSIDECaspase-3HYDROGEN PEROXIDE TETRACYCLINE Transcription factor AP-1 Glutamate racemase REPARIXIN Serotonin (5-HT) receptor Interleukin-8 receptor A ONDANSETRON AZITHROMYCIN Vasopressin V1 receptor Cyclin-dependent kinase 1/cyclin B Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 Smoothened homologNAVITOCLAX SILMITASERTIB VASOPRESSIN AMSACRINEDNA topoisomerase II IVERMECTINalpha EPIRUBICINAMILORIDE HYDROCHLORIDE HYDROCHLORIDE VISMODEGIBBcl2-antagonist of cell death (BAD) MIDOSTAURIN CANNABIDIOL ICLAPRIM CLARITHROMYCIN IRINOTECAN HYDROCHLORIDE HYDRATE VINCRISTINELEUCOVORIN SULFATE CALCIUM DNA topoisomerase II TELITHROMYCINCARBOPLATIN CEFDITOREN PIVOXIL BENFOTIAMINETERIPARATIDE RIFAMYCIN RIFAXIMIN GLUTATHIONE BENZALKONIUM CHLORIDE Mammalian target of Rapamycin (mTORC1) CLINDAMYCIN BETAMETHASONEDONEPEZILMEPARTRICIN HYDROCHLORIDE RUTIN c-Jun
    [Show full text]
  • Characterisation of L-Cell Secretory Mechanisms and Colonic
    Characterisation of L -cell secretory mechanisms and colonic enteroendocrine cell subpopulations Lawrence Billing Downing College, Cambridge This dissertation is submitted for the degree of Doctor of Philosophy September 2018 Abstract Enteroendocrine cells (EECs) are chemosensitive cells of the gastrointestinal epithelium that exert a wide range of physiological effects via production and secretion of hormones in response to ingested nutrients, bacterial metabolites and systemic signals. Glucagon-like peptide-1 (GLP-1) is one such hormone secreted from so-called L-cells found in both the small and large intestines. GLP-1 exerts an anorexigenic effect and together with glucose- dependent insulinotropic polypeptide (GIP), restores postprandial normoglycaemia through the incretin effect. These effects are exploited by GLP-1 analogues in the treatment of type 2 diabetes. GLP-1 may also contribute to weight-loss and remission of type 2 diabetes following bariatric surgery which increases postprandial GLP-1 excursions. Here we investigated stimulus secretion coupling in L-cells. A novel 2D culture system from murine small intestinal organoids was established as an in vitro model. This was used to characterise synergistic stimulation of GLP-1 secretion in response to concomitant stimulation by bile acids through the Gs-protein coupled receptor GPBAR1 and free fatty acids through the Gq-coupled receptor FFAR1. Roughly half of colonic, but not small intestinal, L-cells co-produce the orexigenic peptide insulin-like peptide 5 (INSL5). This hitherto poorly examined subpopulation of L-cells was characterised through transcriptomic analysis, intracellular calcium imaging (using a novel GCaMP6F-based transgenic mouse model), LC/MS peptide quantification and 3D super resolution microscopy (3D-SIM).
    [Show full text]
  • RT² Profiler PCR Array (384-Well Format) Mouse G Protein Coupled Receptors 384HT
    RT² Profiler PCR Array (384-Well Format) Mouse G Protein Coupled Receptors 384HT Cat. no. 330231 PAMM-3009ZE For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Applied Biosystems® models 7900HT (384-well block), Format E ViiA™ 7 (384-well block); Bio-Rad CFX384™ RT² Profiler PCR Array, Roche® LightCycler® 480 (384-well block) Format G Description The Mouse G Protein Coupled Receptors 384HT RT² Profiler™ PCR Array profiles the expression of a comprehensive panel of 370 genes encoding the most important G Protein Coupled Receptors (GPCR). GPCR regulate a number of normal biological processes and play roles in the pathophysiology of many diseases upon dysregulation of their downstream signal transduction activities. As a result, they represent 30 percent of the targets for all current drug development. Developing drug screening assays requires a survey of which GPCR the chosen cell-based model system expresses, to determine not only the expression of the target GPCR, but also related GPCR to assess off-target side effects. Expression of other unrelated GPCR (even orphan receptors whose ligand are unknown) may also correlate with off-target side effects. The ligands that bind and activate the receptors on this array include neurotransmitters and neuropeptides, hormones, chemokines and cytokines, lipid signaling molecules, light-sensitive compounds, and odorants and pheromones. The normal biological processes regulated by GPCR include, but are not limited to, behavioral and mood regulation (serotonin, dopamine, GABA, glutamate, and other neurotransmitter receptors), autonomic (sympathetic and parasympathetic) nervous system transmission (blood pressure, heart rate, and digestive processes via hormone receptors), inflammation and immune system regulation (chemokine receptors, histamine receptors), vision (opsins like rhodopsin), and smell (olfactory receptors for odorants and vomeronasal receptors for pheromones).
    [Show full text]
  • SSTR3 Is a Putative Target for the Medical Treatment of Gonadotroph Adenomas of the Pituitary
    M Lee et al. Somatostatin receptors in 22:1 111–119 Research gonadotroph adenomas SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary Misu Lee, Amelie Lupp1, Nigel Mendoza2, Niamh Martin3, Rudi Beschorner4, Ju¨rgen Honegger5,Ju¨rgen Schlegel6, Talia Shively3, Elke Pulz, Stefan Schulz1, Federico Roncaroli3 and Natalia S Pellegata Correspondence Institute of Pathology, Helmholtz Zentrum Mu¨ nchen, D-85764 Neuherberg, Germany should be addressed 1Department of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany to N S Pellegata; F Roncaroli 2Departments of Neurosurgery 3Medicine, Imperial College, St Dunstans Road, London W6 8RP, UK Emails 4Department of Neuropathology, Institute for Pathology and Neuropathology 5Department of Neurosurgery, natalia.pellegata@ University of Tu¨ bingen, Tu¨ bingen, Germany helmholtz-muenchen.de; 6Institute of Pathology, Technical University of Munich, Mu¨ nchen, Germany [email protected] Abstract Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not Key Words amenable to complete surgical resection. Radiotherapy is the only post-operative option for " somatostatin receptors patients with large invasive or recurrent lesions. No medical treatment is available for these " gonadotroph adenoma patients. The somatostatin analogs (SSAs) octreotide and lanreotide that preferentially " aggressive adenoma target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted " pasireotide that the expression of specific SSTR subtypes determines the response to SSAs. Given that Endocrine-Related Cancer previous studies on mRNA and protein expression of SSTRs in GPAs have generated conflicting results, we investigated the expression of SSTR2, SSTR3, and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well-characterized cohort of 108 patients with GPAs.
    [Show full text]