DOCSLIB.ORG

Expression of Nicotinic Acetylcholine Receptor Subunit Genes in Non–Small-Cell Lung Cancer Reveals Differences Between Smokers and Nonsmokers

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Expression of Nicotinic Acetylcholine Receptor Subunit Genes in Non–Small-Cell Lung Cancer Reveals Differences Between Smokers and Nonsmokers Research Article Expression of Nicotinic Acetylcholine Receptor Subunit Genes in Non–Small-Cell Lung Cancer Reveals Differences between Smokers and Nonsmokers David Chi-leung Lam,1,2 Luc Girard,4 Ruben Ramirez,4 Wing-shun Chau,3 Wai-sing Suen,3 Shelley Sheridan,4 Vicky P.C. Tin,2 Lap-ping Chung,2 Maria P. Wong,2 Jerry W. Shay,5 Adi F. Gazdar,4 Wah-kit Lam,1 and John D. Minna4 Departments of 1Medicine and 2Pathology, University of Hong Kong; 3Cardiothoracic Surgical Unit, The Grantham Hospital, HKSAR, China; and 4Hamon Center for Therapeutic Oncology Research and 5Department of Cell Biology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas Abstract could also participate in lung cancer pathogenesis by activating Nicotine and its derivatives, by binding to nicotinic acetyl- signal transduction pathways such as the Akt pathway (1). One choline receptors (nAChR) on bronchial epithelial cells, can model could be that nicotine by stimulating nicotinic AChRs regulate cellular proliferation and apoptosis via activating the (nAChR) would activate Akt in lung epithelial cells and perhaps Akt pathway. Delineation of nAChR subtypes in non–small-cell stimulate cell proliferation and/or overcome apoptotic responses lung cancers (NSCLC) may provide information for prevention engendered by carcinogen exposure (1). If this model is true, then or therapeutic targeting. Expression of nAChR subunit genes one may ask whether lung tumors have different nAChR expression in 66 resected primary NSCLCs, 7 histologically non-involved patterns compared with normal lung tissues and whether lung lung tissues, 13 NSCLC cell lines, and 6 human bronchial cancers arising in smokers have different patterns compared with epithelial cell lines (HBEC) was analyzed with quantitative never smokers. Such differences would provide additional infor- PCR and microarray analysis. Five nonmalignant HBECs were mation that nicotine is playing a role via the nAChRs in lung cancer exposed to nicotine in vitro to study the variation of nAChR pathogenesis. In recent decades, there have been an increasing subunit gene expression with nicotine exposure and removal. proportion of female nonsmokers compared with male smokers in NSCLCs from nonsmokers showed higher expression of nAChR patients with lung cancer (2). It is possible that both gender and A6(P < 0.001) and B3(P = 0.007) subunit genes than those smoking, or an interaction of both factors, are playing roles in lung from smokers, adjusted for gender. In addition, nAChR A4 carcinogenesis. Differences between men and women may also (P < 0.001) and B4(P = 0.029) subunit gene expression showed make them respond to tobacco smoke in different ways, and lung significant difference between NSCLCs and normal lung. Using tumors derived from male smokers and female nonsmokers may Affymetrix GeneChip U133 Sets, 65 differentially expressed have adopted different carcinogenic pathways. Thus, it would be genes associated with NSCLC nonsmoking nAChR A6B3 important to analyze the role of nAChR expression in the context of phenotype were identified, which gave high sensitivity and gender as well. specificity of prediction. nAChR A1, A5, and A7 showed AChRs are divided into nicotinic (nAChR) and muscarinic significant reversible changes in expression levels in HBECs (mAChR) subtypes. nAChRs are further subdivided into neuronal or upon nicotine exposure. We conclude that between NSCLCs muscle subtypes, which could also be present in nonneuronal or from smokers and nonsmokers, different nAChR subunit gene non-muscle tissues. Neuronal nAChRs are composed of different h h h expression patterns were found, and a 65-gene expression subunits including a1, a2, a3, a4, a5, a6, a7, a9, a10, 1, 2, 3, or h h signature was associated with nonsmoking nAChR A6B3 4. In addition to these different a and subunits, the muscle type y q expression. Finally, nicotine exposure in HBECs resulted in nAChR may also contain , , and g subunits. Genes encoding for reversible differences in nAChR subunit gene expression. individual nAChR subunit are named CHRNA1, CHRNA2, CHRNA3, These results further implicate nicotine in bronchial carcino- CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNA9, and CHRNA10 for genesis and suggest targeting nAChRs for prevention and the a subunits and CHRNB1, CHRNB2, CHRNB3, and CHRNB4 for h therapy in lung cancer. [Cancer Res 2007;67(10):4638–47] the subunits. nAChRs are found to be present throughout the central nervous system (CNS) and in nonneuronal tissues, such as Introduction a3, a5, and a7 in bronchial epithelium (3, 4); a4 in alveolar epithelial cells (4); and a3, a5, a7, h2, and h4 in pulmonary Tobacco smoking is the major cause of lung cancer, and nicotine neuroendocrine cells and human small cell lung cancer (SCLC) cell in tobacco smoke leads to both addiction and further metabolism lines (5–8), skin keratinocytes (9), vascular tissues (10), and human into potent carcinogen(s). In addition, recent discoveries of lymphocytes (11). nAChR holoreceptor is a pentamer consisting of functional acetylcholine receptors (AChR) on lung epithelial cells five homologous or different nAChR subunits surrounding a ligand- and lung tumors raise the question of whether exposure to nicotine gated channel (12) that responds to binding by ligands such as acetylcholine, nicotine, or its highly carcinogenic derivative 4(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK; ref. 13). Neu- Requests for reprints: John D. Minna, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, 6000 Harry ronal nAChR consists of only two types of subunits: either a Hines Boulevard, Dallas, TX 75390-8593. Phone: 214-648-4900; Fax: 214-648-4940; combination of a and h subunits or five copies of the same a E-mail: [email protected]. h I2007 American Association for Cancer Research. subunits (14). Both the a and subunits are thought to contribute doi:10.1158/0008-5472.CAN-06-4628 to the physiologic properties of nAChR, where a subunit contains Cancer Res 2007; 67: (10). May 15, 2007 4638 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2007 American Association for Cancer Research. Nicotinic Acetylcholine Receptors in Lung Cancer the principal sites for agonist binding, such as acetylcholine, and h (NSCLC) specimens and 14 normal lungs tissues. NSCLC tumor specimens subunits are believed to regulate the rate of binding and were collected from Hong Kong Chinese patients undergoing surgical dissociation by agonists (15). Functional receptors in the brain resection. Normal lung tissues used in this study were collected from are composed mainly of a4h2, a4a5h2, a6h2h3, a6h3, a4a6h2h3, patients with lung cancer undergoing surgical resection, and specimens were reviewed to show no tumor involvement. Written informed consent and a7 (16, 17). In fact, a4h2 in the brain is thought to be h for tumor and normal lung tissues collection were obtained from patients responsible for nicotine addiction (18, 19). a6 associated with 2 recruited before surgery, and ethics approval for study protocol was h and 3, a3ora4 is present in dopaminergic and adrenergic obtained from the local Institutional Review Board of the University of neurons in the brain (20); and a6h3, in particular, is a functional Hong Kong (HKU)/Hong Kong Hospital Authority Hong Kong West Cluster. nAChR (21). Receptor affinity for nicotine varies with different The demographic characteristics of these lung cancer patients, including composition of nAChR subunits (20). Transfection studies have their age, gender, smoking habits, and tumor-node-metastasis pathologic shown that the ratio of a/h subunits in nAChRs depends on the staging information, are summarized in Table 1. Nonsmokers were patients ratio of expression of the encoding nAChR subunit genes (22). who have never smoked for their lifetime. Smokers included patients who nAChRs were first implicated in the growth regulation of lung have been current active chronic smokers before surgery and patients who have been daily smoking for more than 6 months in the past but have quit cancer when nicotine was found to stimulate DNA synthesis in smoking at the time of surgery. All 66 NSCLC tumors collected were human SCLC cell lines (23), and this was supported by subsequent included in quantitative PCR, and 49 (all primary lung adenocarcinomas) of identification that the receptor involved was nAChR a7 (7, 24). We these 66 specimens were used for microarray studies; in addition, of the 14 have previously shown that lung cancer cells expressed nAChR, and normal lung tissue specimens, 9 were used for microarray analysis, whereas that nicotine, at concentrations found in smokers, blocked the 7 of them were included in quantitative PCR analysis (two normal lung induction of apoptosis in lung cancer cells (25); whereas West et al. tissue specimens were used in both microarray analysis and quantitative showed that activation of nAChR resulted in downstream PCR analysis). activation of the Akt pathway (1), protein kinase C pathway, and A panel of 13 NSCLC cell lines (9 NCI-H lung cancer cell lines and 4 the mitogen-activated protein kinase (MAPK) pathways, leading to HKULC lung cancer cell lines) were used in this study, and total RNA was extracted for quantitative PCR (Table 1). The NCI-H lung cancer cell lines inhibition of apoptosis and promotion of growth and proliferation (all were NSCLC lines: H1437, H1648, H1770, H1819, H1993, H2009, H2087, in human bronchial epithelial cells (HBEC; refs. 1, 25). H2122, and H2347) were maintained at the Hamon Center for Therapeutic a In the brain, nAChR 7 showed paradoxical up-regulation in Oncology Research, University of Texas Southwestern Medical Center at response to chronic exposure to nicotine, whereas other nAChR Dallas (31) and have been deposited in the American Type Culture subunits were down-regulated. It has also been shown that the Collection (ATCC) repository (32). The HKULC cell lines (HKULC1–4) were nAChR a7 in the lungs of monkeys is up-regulated by exposure to newly established lung adenocarcinomas from Hong Kong Chinese nicotine (26).
Load more

Recommended publications
  • Release Β ATP-Induced IL-1 and Canonical Nicotinic Agonists Inhibit Phosphocholine-Modified Macromolecules
    Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release This information is current as Andreas Hecker, Mira Küllmar, Sigrid Wilker, Katrin of September 24, 2021. Richter, Anna Zakrzewicz, Srebrena Atanasova, Verena Mathes, Thomas Timm, Sabrina Lerner, Jochen Klein, Andreas Kaufmann, Stefan Bauer, Winfried Padberg, Wolfgang Kummer, Sabina Janciauskiene, Martin Fronius, Elke K. H. Schweda, Günter Lochnit and Veronika Grau Downloaded from J Immunol 2015; 195:2325-2334; Prepublished online 22 July 2015; doi: 10.4049/jimmunol.1400974 http://www.jimmunol.org/content/195/5/2325 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2015/07/22/jimmunol.140097 Material 4.DCSupplemental References This article cites 42 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/195/5/2325.full#ref-list-1 by guest on September 24, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Download Download
    Supplementary Figure S1. Results of flow cytometry analysis, performed to estimate CD34 positivity, after immunomagnetic separation in two different experiments. As monoclonal antibody for labeling the sample, the fluorescein isothiocyanate (FITC)- conjugated mouse anti-human CD34 MoAb (Mylteni) was used. Briefly, cell samples were incubated in the presence of the indicated MoAbs, at the proper dilution, in PBS containing 5% FCS and 1% Fc receptor (FcR) blocking reagent (Miltenyi) for 30 min at 4 C. Cells were then washed twice, resuspended with PBS and analyzed by a Coulter Epics XL (Coulter Electronics Inc., Hialeah, FL, USA) flow cytometer. only use Non-commercial 1 Supplementary Table S1. Complete list of the datasets used in this study and their sources. GEO Total samples Geo selected GEO accession of used Platform Reference series in series samples samples GSM142565 GSM142566 GSM142567 GSM142568 GSE6146 HG-U133A 14 8 - GSM142569 GSM142571 GSM142572 GSM142574 GSM51391 GSM51392 GSE2666 HG-U133A 36 4 1 GSM51393 GSM51394 only GSM321583 GSE12803 HG-U133A 20 3 GSM321584 2 GSM321585 use Promyelocytes_1 Promyelocytes_2 Promyelocytes_3 Promyelocytes_4 HG-U133A 8 8 3 GSE64282 Promyelocytes_5 Promyelocytes_6 Promyelocytes_7 Promyelocytes_8 Non-commercial 2 Supplementary Table S2. Chromosomal regions up-regulated in CD34+ samples as identified by the LAP procedure with the two-class statistics coded in the PREDA R package and an FDR threshold of 0.5. Functional enrichment analysis has been performed using DAVID (http://david.abcc.ncifcrf.gov/)
    [Show full text]
  • Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed Hipscs To
    Hindawi Publishing Corporation Stem Cells International Volume 2013, Article ID 784629, 25 pages http://dx.doi.org/10.1155/2013/784629 Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny Leonhard Linta,1 Marianne Stockmann,1 Qiong Lin,2 André Lechel,3 Christian Proepper,1 Tobias M. Boeckers,1 Alexander Kleger,3 and Stefan Liebau1 1 InstituteforAnatomyCellBiology,UlmUniversity,Albert-EinsteinAllee11,89081Ulm,Germany 2 Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany 3 Department of Internal Medicine I, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany Correspondence should be addressed to Alexander Kleger; [email protected] and Stefan Liebau; [email protected] Received 31 January 2013; Accepted 6 March 2013 Academic Editor: Michael Levin Copyright © 2013 Leonhard Linta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated.
    [Show full text]
  • Stem Cells and Ion Channels
    Stem Cells International Stem Cells and Ion Channels Guest Editors: Stefan Liebau, Alexander Kleger, Michael Levin, and Shan Ping Yu Stem Cells and Ion Channels Stem Cells International Stem Cells and Ion Channels Guest Editors: Stefan Liebau, Alexander Kleger, Michael Levin, and Shan Ping Yu Copyright © 2013 Hindawi Publishing Corporation. All rights reserved. This is a special issue published in “Stem Cells International.” All articles are open access articles distributed under the Creative Com- mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board Nadire N. Ali, UK Joseph Itskovitz-Eldor, Israel Pranela Rameshwar, USA Anthony Atala, USA Pavla Jendelova, Czech Republic Hannele T. Ruohola-Baker, USA Nissim Benvenisty, Israel Arne Jensen, Germany D. S. Sakaguchi, USA Kenneth Boheler, USA Sue Kimber, UK Paul R. Sanberg, USA Dominique Bonnet, UK Mark D. Kirk, USA Paul T. Sharpe, UK B. Bunnell, USA Gary E. Lyons, USA Ashok Shetty, USA Kevin D. Bunting, USA Athanasios Mantalaris, UK Igor Slukvin, USA Richard K. Burt, USA Pilar Martin-Duque, Spain Ann Steele, USA Gerald A. Colvin, USA EvaMezey,USA Alexander Storch, Germany Stephen Dalton, USA Karim Nayernia, UK Marc Turner, UK Leonard M. Eisenberg, USA K. Sue O’Shea, USA Su-Chun Zhang, USA Marina Emborg, USA J. Parent, USA Weian Zhao, USA Josef Fulka, Czech Republic Bruno Peault, USA Joel C. Glover, Norway Stefan Przyborski, UK Contents Stem Cells and Ion Channels, Stefan Liebau,
    [Show full text]
  • Ion Channels
    UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
    [Show full text]
  • Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence
    G C A T T A C G G C A T genes Article Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence Lingjun Zuo 1, Rolando Garcia-Milian 2, Xiaoyun Guo 1,3,4,*, Chunlong Zhong 5,*, Yunlong Tan 6, Zhiren Wang 6, Jijun Wang 3, Xiaoping Wang 7, Longli Kang 8, Lu Lu 9,10, Xiangning Chen 11,12, Chiang-Shan R. Li 1 and Xingguang Luo 1,6,* 1 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; [email protected] (L.Z.); [email protected] (C.-S.R.L.) 2 Curriculum & Research Support Department, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, CT 06510, USA; [email protected] 3 Shanghai Mental Health Center, Shanghai 200030, China; [email protected] 4 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA 5 Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China 6 Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing 100096, China; [email protected] (Y.T.); [email protected] (Z.W.) 7 Department of Neurology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai 200080, China; [email protected] 8 Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Diseases of Tibet Autonomous Region, Xizang Minzu University School of Medicine, Xianyang, Shanxi 712082, China; [email protected] 9 Provincial Key Laboratory for Inflammation and Molecular Drug Target, Medical
    [Show full text]
  • A Bioinformatics Model of Human Diseases on the Basis Of
    SUPPLEMENTARY MATERIALS A Bioinformatics Model of Human Diseases on the basis of Differentially Expressed Genes (of Domestic versus Wild Animals) That Are Orthologs of Human Genes Associated with Reproductive-Potential Changes Vasiliev1,2 G, Chadaeva2 I, Rasskazov2 D, Ponomarenko2 P, Sharypova2 E, Drachkova2 I, Bogomolov2 A, Savinkova2 L, Ponomarenko2,* M, Kolchanov2 N, Osadchuk2 A, Oshchepkov2 D, Osadchuk2 L 1 Novosibirsk State University, Novosibirsk 630090, Russia; 2 Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia; * Correspondence: [email protected]. Tel.: +7 (383) 363-4963 ext. 1311 (M.P.) Supplementary data on effects of the human gene underexpression or overexpression under this study on the reproductive potential Table S1. Effects of underexpression or overexpression of the human genes under this study on the reproductive potential according to our estimates [1-5]. ↓ ↑ Human Deficit ( ) Excess ( ) # Gene NSNP Effect on reproductive potential [Reference] ♂♀ NSNP Effect on reproductive potential [Reference] ♂♀ 1 increased risks of preeclampsia as one of the most challenging 1 ACKR1 ← increased risk of atherosclerosis and other coronary artery disease [9] ← [3] problems of modern obstetrics [8] 1 within a model of human diseases using Adcyap1-knockout mice, 3 in a model of human health using transgenic mice overexpressing 2 ADCYAP1 ← → [4] decreased fertility [10] [4] Adcyap1 within only pancreatic β-cells, ameliorated diabetes [11] 2 within a model of human diseases
    [Show full text]
  • Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology
    brain sciences Review Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology Andrea Becchetti 1,* , Laura Clara Grandi 1 , Giulia Colombo 1 , Simone Meneghini 1 and Alida Amadeo 2 1 Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milano, Italy; [email protected] (L.C.G.); [email protected] (G.C.); [email protected] (S.M.) 2 Department of Biosciences, University of Milano, 20133 Milano, Italy; [email protected] * Correspondence: [email protected] Received: 13 October 2020; Accepted: 21 November 2020; Published: 25 November 2020 Abstract: Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic focal seizures, mainly arising in the neocortex during non-rapid eye movements (NREM) sleep. The familial form is autosomal dominant SHE (ADSHE), which can be caused by mutations in genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR), Na+-gated K+ channels, as well as non-channel signaling proteins, such as components of the gap activity toward rags 1 (GATOR1) macromolecular complex. The causative genes may have different roles in developing and mature brains. Under this respect, nicotinic receptors are paradigmatic, as different pathophysiological roles are exerted by distinct nAChR subunits in adult and developing brains. The widest evidence concerns α4 and β2 subunits. These participate in heteromeric nAChRs that are major modulators of excitability in mature neocortical circuits as well as regulate postnatal synaptogenesis. However, growing evidence implicates mutant α2 subunits in ADSHE, which poses interpretive difficulties as very little is known about the function of α2-containing (α2*) nAChRs in the human brain.
    [Show full text]
  • Structural Analysis of Pathogenic Missense Mutations in GABRA2 and Identification of a Novel De Novo Variant in the Desensitization Gate
    Received: 22 October 2019 | Revised: 29 November 2019 | Accepted: 10 December 2019 DOI: 10.1002/mgg3.1106 ORIGINAL ARTICLE Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate Alba Sanchis-Juan1,2 | Marcia A. Hasenahuer3,4 | James A. Baker3 | Amy McTague5 | Katy Barwick5 | Manju A. Kurian5 | Sofia T. Duarte6 | NIHR BioResource | Keren J. Carss1,2 | Janet Thornton3 | F. Lucy Raymond2,4 1Department of Haematology, University of Cambridge, NHS Blood and Transplant Abstract Centre, Cambridge, UK Background: Cys-loop receptors control neuronal excitability in the brain and their 2NIHR BioResource, Cambridge dysfunction results in numerous neurological disorders. Recently, six missense vari- University Hospitals NHS Foundation ants in GABRA2, a member of this family, have been associated with early infantile Trust, Cambridge Biomedical Campus, Cambridge, UK epileptic encephalopathy (EIEE). We identified a novel de novo missense variant 3European Molecular Biology Laboratory, in GABRA2 in a patient with EIEE and performed protein structural analysis of the European Bioinformatics Institute, seven variants. Wellcome Genome Campus, Hinxton, . Cambridge, UK Methods: The novel variant was identified by trio whole-genome sequencing We 4Department of Medical Genetics, performed protein structural analysis of the seven variants, and compared them to Cambridge Institute for Medical Research, previously reported pathogenic mutations at equivalent positions in other Cys-loop University of Cambridge, Cambridge, UK receptors. Additionally, we studied the distribution of disease-associated variants in 5Developmental Neurosciences, Great the transmembrane helices of these proteins. Ormond Street Institute of Child Health, University College London, London, UK Results: The seven variants are in the transmembrane domain, either close to the de- 6Hospital Dona Estefânia, Centro Hospitalar sensitization gate, the activation gate, or in inter-subunit interfaces.
    [Show full text]
  • Resequencing of Nicotinic Acetylcholine Receptor Genes and Association of Common and Rare Variants with the Fagerstro¨M Test for Nicotine Dependence
    Neuropsychopharmacology (2010) 35, 2392–2402 & 2010 Nature Publishing Group All rights reserved 0893-133X/10 $32.00 www.neuropsychopharmacology.org Resequencing of Nicotinic Acetylcholine Receptor Genes and Association of Common and Rare Variants with the Fagerstro¨m Test for Nicotine Dependence 1,4 1 2 2 1 Jennifer Wessel , Sarah M McDonald , David A Hinds , Renee P Stokowski , Harold S Javitz , 2 1 2 1 2 1 Michael Kennemer , Ruth Krasnow , William Dirks , Jill Hardin , Steven J Pitts , Martha Michel , 1 2 3 1 ,1 Lisa Jack , Dennis G Ballinger , Jennifer B McClure , Gary E Swan and Andrew W Bergen* 1 2 3 Center for Health Sciences, SRI International, Menlo Park, CA, USA; Perlegen Sciences, Mountain View, CA, USA; Group Health Research 4 Institute, Seattle, WA, USA; Department of Public Health, Indiana University School of Medicine, Indianapolis, IN, USA Common single-nucleotide polymorphisms (SNPs) at nicotinic acetylcholine receptor (nAChR) subunit genes have previously been associated with measures of nicotine dependence. We investigated the contribution of common SNPs and rare single-nucleotide variants (SNVs) in nAChR genes to Fagerstro¨m test for nicotine dependence (FTND) scores in treatment-seeking smokers. Exons of 10 genes were resequenced with next-generation sequencing technology in 448 European-American participants of a smoking cessation trial, and CHRNB2 and CHRNA4 were resequenced by Sanger technology to improve sequence coverage. A total of 214 SNP/SNVs were identified, of which 19.2% were excluded from analyses because of reduced completion rate, 73.9% had minor allele frequencies o5%, and 48.1% were novel relative to dbSNP build 129.
    [Show full text]
  • Lung Cancer and Nicotine
    aphy & S gr ep to a a ra t m i o o r n h T C e Bharti and Yashila, J Chromatogr Sep Tech 2016, 7:2 f c o h Journal of Chromatography l n a i DOI: 10.4172/2157-7064.1000319 q n u r e u s o J Separation Techniques ISSN: 2157-7064 Review Article OpenOpen Access Access Lung Cancer and Nicotine Bharti M1* and Yashila G2 1National Institute of Pharmaceutical Education and Research, Mohali, Punjab-160 062, India 2Department of Biotechnology, Thapar University, Patiala, Punjab-147 002, India Abstract Nicotine present in smoking and tobacco is major cause of occurrence of lung cancer. The basic nature of nicotine helps in easy absorption through lungs. The binding of nicotine and its derivatives to Nicotinic Acetylcholine Receptor results in significant polymorphic mutations in genes coding the subunits of receptors in various populations like Asian and Caucasians which increases the susceptibility of lung cancer in these populations. Keywords: Nicotine; Lung cancer; Nicotine acetylcholine receptors competitively to the Nicotine Acetylcholine Receptor (nAChRs) present in brain as well as in lungs [6]. Nicotine is get metabolized in Introduction liver along with lungs and kidneys and responsible for the production Lung cancer is the third most common cancer after prostate gland of highly carcinogenic intermediates and by-products which also and breast cancer. A study has been reported 63,000 deaths per year in annex to the Nicotine Acetylcholine Receptor (nAChRs) and cause India due to the lung cancer [1]. Although, there must be numerous alterations in the receptors.
    [Show full text]