DOCSLIB.ORG

Ion Channel Pharmacology

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ion Channel Pharmacology Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Ion Channel Pharmacology Diana Conte Camerino, Domenico Tricarico, and Jean-François Desaphy Pharmacology Division, Department of Pharmacobiology, School of Pharmacy, University of Bari, Bari, Italy Summary: Because ion channels are involved in many cellular tions have demonstrated that channel mutations can either in- processes, drugs acting on ion channels have long been used for crease or decrease affinity for the drug, modifying its potential the treatment of many diseases, especially those affecting elec- therapeutic effect. Together with the discovery of channel gene trically excitable tissues. The present review discusses the phar- polymorphisms that may affect drug pharmacodynamics, these macology of voltage-gated and neurotransmitter-gated ion findings highlight the need for pharmacogenetic research to channels involved in neurologic diseases, with emphasis on allow identification of drugs with more specific effects on neurologic channelopathies. With the discovery of ion chan- channel isoforms or mutants, to increase efficacy and reduce nelopathies, the therapeutic value of many basic drugs targeting side effects. With a greater understanding of channel genetics, ion channels has been confirmed. The understanding of the structure, and function, together with the identification of novel genotype–phenotype relationship has highlighted possible ac- primary and secondary channelopathies, the number of ion tion mechanisms of other empirically used drugs. Moreover, channel drugs for neurologic channelopathies will increase sub- other ion channels have been pinpointed as potential new Key Words: drug targets. With regards to therapy of channelopathies, ex- stantially. Voltage-gated, neurotransmitter-gated, perimental investigations of the intimate drug–channel interac- ion channel, drug therapy, channelopathy, pharmacogenetics. INTRODUCTION channels.1 Beyond their usefulness in the clinical setting, natural ion channel ligands, especially toxins with high Ion channels are involved in many, if not all, cellular functions and are altered in many pathological conditions binding affinity, have also largely contributed to the dis- either indirectly or directly, as in the channelopathies. It covery of the various ion channels and the understanding is not surprising, therefore, that drugs targeting ion chan- of their structure and function long before their molecu- nels constitute important therapeutic interventions for a lar identification. number of diseases. The use of ion channel modulators Historically, the role of ion channels was most obvious as drugs was operative long before their existence be- in the membrane of electrically excitable cells, such as came known. Ion channel function is modulated by many the neuron, the cardiac myocyte, and the skeletal muscle natural agents of the animal and plant kingdoms, which fiber. Consequently, a number of drugs able to modulate contribute to the dangerous effects of poisons or the cell excitability by acting on voltage-gated or neurotrans- beneficial effects of medicinal herbs. Once isolated, mitter-gated ion channels in these tissues have reached these lead compounds have served as the basis for the blockbuster status in the pharmaceutical industry, gener- synthesis of more specific ligands with fewer side ef- ating large profits. Examples are the antiepileptic drugs fects. For instance, cocaine extracted from coca leaves (AEDs), which include blockers of voltage-gated sodium entered clinical practice in the 1880s for its analgesic and calcium channels, agonists of GABAA receptors, properties, but the occurrence of CNS and cardiovascular and, more recently, openers of potassium channels and toxicity led medicinal chemists to synthesize new deriv- antagonists of AMPA and NMDA glutamate receptors. atives, thus giving rise to the pharmaceutical class of Today more than 400 genes are known that encode local anesthetics, which are selective blockers of sodium even more ion channel subunits due to alternative splic- ing, each subunit being likely the target of many phar- macological agents. Covering all drugs acting on ion Address correspondence and reprint requests to: Diana Conte Cam- channels is beyond the scope of this review, which will erino, Ph.D., Sezione di Farmacologia, Dipartimento FarmacoBio- logico, Facoltà di Farmacia, Università degli Studi di Bari, via Orabona instead focus mainly on drugs acting on ion channels 4 – CAMPUS, I-70125, Bari, Italy. E-mail: [email protected]. involved in neurologic disorders and especially their use 184 Vol. 4, 184–198, April 2007 © The American Society for Experimental NeuroTherapeutics, Inc. ION CHANNEL PHARMACOLOGY 185 in channelopathies. The sections that follow each detail channels participate to the repolarization of the postsyn- the pharmacology of an ion channel family. In addition, aptic action potential.2,3 Kv3.1Ϫ/Ϫ mice show impaired a synopsis of drug information for the neurologic chan- motor skills and reduced muscle contraction force. Dou- nelopathies is provided in Table 1. ble Kv3.1/Kv3.3 knockout mice show ataxia, myoclo- nus, and other neurological abnormalities. Kv channels are also involved in neurological symptoms observed in PHARMACOLOGY OF POTASSIUM paraneoplastic neurological syndromes, which are re- CHANNELS mote effects of cancer with an autoimmune response 5 ϩ against CNS and peripheral nervous antigens. - K channels are classified on the basis of the primary In neuro myotonia associated with limbic encephalitis and small amino acid sequence of the pore-containing unit (␣-sub- ϩ cell lung cancer cells (SCLC), function of Kv1.1/Kv1.2 unit) into three major families: 1) voltage-gated K channels is progressively lost because of an abnormally channels (Kv) containing six or seven transmembrane enhanced turnover and degradation of the proteins. The regions with a single pore, including also KCNQ, hERG, 2ϩ ϩ immune system is also modulated by the Kv1.3 channel, eag, and the Ca -activated K channels; 2) inward which is expressed in many cells involved in immune rectifiers (Kir) containing only two transmembrane re- 5 gions and a single pore; and 3) two-pore tandem Kϩ responses and is a drug target. Kv channel blockers. ϩ channels containing four transmembrane segments with The voltage-gated K channels have been investigated through the use of peptide toxins two pores. The pore subunits coassemble with auxiliary from animals and plants, such as dendrototoxins, kali- subunits, affecting their pharmacological responses and toxin, hongotoxin, margatoxin, and others that block the modulation by second messengers. channel pore at picomolar to nanomolar concentrations Pharmacology of voltage-gated potassium and serve as tools for the analysis of their structure– (Kv) channels function relationships. These toxins block Kv1.1–6 2,6 Following the cloning of the four Kϩ channel genes in channel subtypes. Although Kv channels were the first Drosophila, several members of related voltage-gated Kϩ to be molecularly characterized, no selective blockers or channel (Kv) genes were identified in mammals and di- openers are currently available. Tetraethylammonium vided into eight gene families: KCNA (Kv1.1–8), KCNB (TEA) and 4-aminopyridine (4-AP) are classic Kv chan- (Kv2.1–2), KCNC (Kv3.1–4), KCND (Kv4.1–3), KCNF nel blockers, which can discriminate between various (Kv5.1), KCNG (Kv6.1–4), KCNS (Kv9.1–3) and channel subtypes. The Kv1.1, Kv3.1–4, and Kv7.2 chan- KCNV (Kv8.1–3). The Kv1–4 families can form homo- nels are more sensitive to TEA. Kv1.1–5, Kv1.7 and or heteromeric channels with other subunits from within Kv3.1–2 are inhibited by micromolar concentrations of their own family or with the electrically silent families 4-AP, but millimolar concentrations are needed to block (Kv5, Kv6, Kv8, and Kv9). The ␤-subunits of Kv chan- Kv1.6, 1.8, 2.2, 3.3 and Kv4.1–3. nels influence channel properties, trafficking, and drug Other members, such as Kv2.1, Kv3.4, hERG, eag1, responses.2 and KCNQ channels, are insensitive to 4-AP. Several Kv1.1–2 channels are involved in neuronal chan- 4-AP analogs have been tested against Kv channels, and nelopathies. Kv1.1 is expressed in many neurons, motor the order of potency as Kv inhibitors ranks as follows 7 neurons, retina, and heart and skeletal muscle, whereas 3,4-DAP Ͼ 4-AP Ͼ 3-AP Ͼ 2-AP. These drugs cause Kv1.2 is expressed mainly in the cerebellum, hippocam- neuronal firing and release of neurotransmitters such as pus, and thalamus. These low-voltage activated channels, acetylcholine (ACh). Thus, 4-AP and 3,4-diaminopyri- located in the axons of neurons, do not affect the first dine (3,4-DAP) (EU/3/02/124) (25–60 mg/day) are ef- action potential but increase the action potential thresh- fective in those conditions associated with loss or re- old.3 Kv1.1 and Kv1.2 can form heteromultimers impor- duced quantal release of neurotransmitters such as tant for repolarization of the presynapsis in neurons and episodic ataxias, myasthenia gravis (MG), Lambert– skeletal muscle. Eaton myasthenic syndromes (LEMS), and degenerative Loss-of-function mutations of KCNA1 are associated cognitive disorders. with episodic ataxia type 1 (EA1), which is characterized In episodic ataxias type 2 and 6 (EA2 and EA6) the by episodic failure of cerebellar excitation, while hyper- drugs enhance the excitability of spinocerebellar axis excitability of motor neurons is commonly observed. An that is compromised by gain-of-function mutations of
Load more

Recommended publications
  • Journal of Pharmacology and Experimental Therapeutics
    Journal of Pharmacology and Experimental Therapeutics Molecular Determinants of Ligand Selectivity for the Human Multidrug And Toxin Extrusion Proteins, MATE1 and MATE-2K Bethzaida Astorga, Sean Ekins, Mark Morales and Stephen H Wright Department of Physiology, University of Arizona, Tucson, AZ 85724, USA (B.A., M.M., and S.H.W.) Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina NC 27526, USA (S.E.) Supplemental Table 1. Compounds selected by the common features pharmacophore after searching a database of 2690 FDA approved compounds (www.collaborativedrug.com). FitValue Common Name Indication 3.93897 PYRIMETHAMINE Antimalarial 3.3167 naloxone Antidote Naloxone Hydrochloride 3.27622 DEXMEDETOMIDINE Anxiolytic 3.2407 Chlordantoin Antifungal 3.1776 NALORPHINE Antidote Nalorphine Hydrochloride 3.15108 Perfosfamide Antineoplastic 3.11759 Cinchonidine Sulfate Antimalarial Cinchonidine 3.10352 Cinchonine Sulfate Antimalarial Cinchonine 3.07469 METHOHEXITAL Anesthetic 3.06799 PROGUANIL Antimalarial PROGUANIL HYDROCHLORIDE 100MG 3.05018 TOPIRAMATE Anticonvulsant 3.04366 MIDODRINE Antihypotensive Midodrine Hydrochloride 2.98558 Chlorbetamide Antiamebic 2.98463 TRIMETHOPRIM Antibiotic Antibacterial 2.98457 ZILEUTON Antiinflammatory 2.94205 AMINOMETRADINE Diuretic 2.89284 SCOPOLAMINE Antispasmodic ScopolamineHydrobromide 2.88791 ARTICAINE Anesthetic 2.84534 RITODRINE Tocolytic 2.82357 MITOBRONITOL Antineoplastic Mitolactol 2.81033 LORAZEPAM Anxiolytic 2.74943 ETHOHEXADIOL Insecticide 2.64902 METHOXAMINE Antihypotensive Methoxamine
    [Show full text]
  • Paramyotonia Congenita
    Paramyotonia congenita Description Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements. Most people—even those without muscle disease—feel that their muscles do not work as well when they are cold. This effect is dramatic in people with paramyotonia congenita. Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. Some older people with paramyotonia congenita develop permanent muscle weakness that can be disabling. Frequency Paramyotonia congenita is an uncommon disorder; it is estimated to affect fewer than 1 in 100,000 people. Causes Mutations in the SCN4A gene cause paramyotonia congenita. This gene provides instructions for making a protein that is critical for the normal function of skeletal muscle cells. For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of positively charged atoms (ions), including sodium, into skeletal muscle cells. The SCN4A protein forms channels that control the flow of sodium ions into these cells.
    [Show full text]
  • Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls
    toxins Review Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls 1 2 3, 4, , Marie-Line Reynaert , Denis Dupoiron , Edouard Yeramian y, Laurent Marsollier * y and 1, , Priscille Brodin * y 1 France Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France 2 Institut de Cancérologie de l’Ouest Paul Papin, 15 rue André Boquel-49055 Angers, France 3 Unité de Microbiologie Structurale, Institut Pasteur, CNRS, Univ. Paris, F-75015 Paris, France 4 Equipe ATIP AVENIR, CRCINA, INSERM, Univ. Nantes, Univ. Angers, 4 rue Larrey, F-49933 Angers, France * Correspondence: [email protected] (L.M.); [email protected] (P.B.) These three authors contribute equally to this work. y Received: 29 June 2019; Accepted: 3 September 2019; Published: 4 September 2019 Abstract: Pain currently represents the most common symptom for which medical attention is sought by patients. The available treatments have limited effectiveness and significant side-effects. In addition, most often, the duration of analgesia is short. Today, the handling of pain remains a major challenge. One promising alternative for the discovery of novel potent analgesics is to take inspiration from Mother Nature; in this context, the detailed investigation of the intriguing analgesia implemented in Buruli ulcer, an infectious disease caused by the bacterium Mycobacterium ulcerans and characterized by painless ulcerative lesions, seems particularly promising. More precisely, in this disease, the painless skin ulcers are caused by mycolactone, a polyketide lactone exotoxin. In fact, mycolactone exerts a wide range of effects on the host, besides being responsible for analgesia, as it has been shown notably to modulate the immune response or to provoke apoptosis.
    [Show full text]
  • The Mineralocorticoid Receptor Leads to Increased Expression of EGFR
    www.nature.com/scientificreports OPEN The mineralocorticoid receptor leads to increased expression of EGFR and T‑type calcium channels that support HL‑1 cell hypertrophy Katharina Stroedecke1,2, Sandra Meinel1,2, Fritz Markwardt1, Udo Kloeckner1, Nicole Straetz1, Katja Quarch1, Barbara Schreier1, Michael Kopf1, Michael Gekle1 & Claudia Grossmann1* The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important efector of the renin–angiotensin–aldosterone‑system and elicits pathophysiological efects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR‑mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identifed a SNP within the EGFR promoter that modulates MR‑induced EGFR expression. In RNA‑sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to diferential expression of cardiac ion channels, especially of the T‑type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone‑ and EGF‑responsiveness of CACNA1H expression was confrmed in HL‑1 cells by Western blot and by measuring peak current density of T‑type calcium channels. Aldosterone‑induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T‑type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL‑1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an efect on HL‑1 cell diameter, and the extent of this regulation seems to depend on the SNP‑216 (G/T) genotype.
    [Show full text]
  • Calcium-Induced Calcium Release in Noradrenergic Neurons of the Locus Coeruleus
    bioRxiv preprint doi: https://doi.org/10.1101/853283; this version posted November 23, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Calcium-induced calcium release in noradrenergic neurons of the locus coeruleus Hiroyuki Kawano1, Sara B. Mitchell1, Jin-Young Koh1,2,3, Kirsty M. Goodman1,4, and N. Charles Harata1,* 1 Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA, USA 2 Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA 3 Department of Biomedical Engineering, University of Iowa College of Engineering, Iowa City, IA, USA 4 Department of Biology & Biochemistry, University of Bath, Bath, UK * Correspondence to: N. Charles Harata, MD, PhD Department of Molecular Physiology & Biophysics University of Iowa Carver College of Medicine 51 Newton Road, Iowa City, IA 52242, USA Phone: 1-319-335-7820 Fax: 1-319-335-7330 E-mail: [email protected] Number of words: 8620; Number of figures: 12. 1 bioRxiv preprint doi: https://doi.org/10.1101/853283; this version posted November 23, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
    [Show full text]
  • Eslicarbazepine Acetate Longer Procedure No
    European Medicines Agency London, 19 February 2009 Doc. Ref.: EMEA/135697/2009 CHMP ASSESSMENT REPORT FOR authorised Exalief International Nonproprietary Name: eslicarbazepine acetate longer Procedure No. EMEA/H/C/000987 no Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. product Medicinal 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 16 E-mail: [email protected] http://www.emea.europa.eu TABLE OF CONTENTS 1. BACKGROUND INFORMATION ON THE PROCEDURE........................................... 3 1.1. Submission of the dossier ...................................................................................................... 3 1.2. Steps taken for the assessment of the product..................................................................... 3 2. SCIENTIFIC DISCUSSION................................................................................................. 4 2.1. Introduction............................................................................................................................ 4 2.2. Quality aspects ....................................................................................................................... 5 2.3. Non-clinical aspects................................................................................................................ 8 2.4. Clinical aspects....................................................................................................................
    [Show full text]
  • Potassium Channels in Epilepsy
    Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Potassium Channels in Epilepsy Ru¨diger Ko¨hling and Jakob Wolfart Oscar Langendorff Institute of Physiology, University of Rostock, Rostock 18057, Germany Correspondence: [email protected] This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dy- namic, aggravating, or adaptive transcriptional and posttranslational alterations. In these cases, it often remains elusive whether the alteration is causal or merely incidental. With 80 potassium channel types, of which 10% are known to be associated with epilepsies (in humans) or a seizure phenotype (in animals), if genetically mutated, a comprehensive review is a challenging endeavor. This goal may seem all the more ambitious once the data on posttranslational alterations, found both in human tissue from epilepsy patients and in chronic or acute animal models, are included. We therefore summarize the literature, and expand only on key findings, particularly regarding functional alterations found in patient brain tissue and chronic animal models. INTRODUCTION TO POTASSIUM evolutionary appearance of voltage-gated so- CHANNELS dium (Nav)andcalcium (Cav)channels, Kchan- nels are further diversified in relation to their otassium (K) channels are related to epilepsy newer function, namely, keeping neuronal exci- Psyndromes on many different levels, ranging tation within limits (Anderson and Greenberg from direct control of neuronal excitability and 2001; Hille 2001).
    [Show full text]
  • Inherited Neuropathies
    407 Inherited Neuropathies Vera Fridman, MD1 M. M. Reilly, MD, FRCP, FRCPI2 1 Department of Neurology, Neuromuscular Diagnostic Center, Address for correspondence Vera Fridman, MD, Neuromuscular Massachusetts General Hospital, Boston, Massachusetts Diagnostic Center, Massachusetts General Hospital, Boston, 2 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology Massachusetts, 165 Cambridge St. Boston, MA 02114 and The National Hospital for Neurology and Neurosurgery, Queen (e-mail: [email protected]). Square, London, United Kingdom Semin Neurol 2015;35:407–423. Abstract Hereditary neuropathies (HNs) are among the most common inherited neurologic Keywords disorders and are diverse both clinically and genetically. Recent genetic advances have ► hereditary contributed to a rapid expansion of identifiable causes of HN and have broadened the neuropathy phenotypic spectrum associated with many of the causative mutations. The underlying ► Charcot-Marie-Tooth molecular pathways of disease have also been better delineated, leading to the promise disease for potential treatments. This chapter reviews the clinical and biological aspects of the ► hereditary sensory common causes of HN and addresses the challenges of approaching the diagnostic and motor workup of these conditions in a rapidly evolving genetic landscape. neuropathy ► hereditary sensory and autonomic neuropathy Hereditary neuropathies (HN) are among the most common Select forms of HN also involve cranial nerves and respiratory inherited neurologic diseases, with a prevalence of 1 in 2,500 function. Nevertheless, in the majority of patients with HN individuals.1,2 They encompass a clinically heterogeneous set there is no shortening of life expectancy. of disorders and vary greatly in severity, spanning a spectrum Historically, hereditary neuropathies have been classified from mildly symptomatic forms to those resulting in severe based on the primary site of nerve pathology (myelin vs.
    [Show full text]
  • Experiences of Rare Diseases: an Insight from Patients and Families
    Experiences of Rare Diseases: An Insight from Patients and Families Unit 4D, Leroy House 436 Essex Road London N1 3QP tel: 02077043141 fax: 02073591447 [email protected] www.raredisease.org.uk By Lauren Limb, Stephen Nutt and Alev Sen - December 2010 Web and press design www.raredisease.org.uk WordsAndPeople.com About Rare Disease UK Rare Disease UK (RDUK) is the national alliance for people with rare diseases and all who support them. Our membership is open to all and includes patient organisations, clinicians, researchers, academics, industry and individuals with an interest in rare diseases. RDUK was established by Genetic RDUK is campaigning for a Alliance UK, the national charity strategy for integrated service of over 130 patient organisations delivery for rare diseases. This supporting all those affected by would coordinate: genetic conditions, in conjunction with other key stakeholders | Research in November 2008 following the European Commission’s | Prevention and diagnosis Communication on Rare Diseases: | Treatment and care Europe’s Challenges. | Information Subsequently RDUK successfully | Commissioning and planning campaigned for the adoption of the Council of the European into one cohesive strategy for all Union’s Recommendation on patients affected by rare disease in an action in the field of rare the UK. As well as securing better diseases. The Recommendation outcomes for patients, a strategy was adopted unanimously by each would enable the most effective Member State of the EU (including use of NHS resources. the
    [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]
  • Big Pain Assays Aren't a Big Pain with the Raptor Biphenyl LC Column
    Featured Application: 231 Pain Management and Drugs of Abuse Compounds in under 10 Minutes by LC-MS/MS Big Pain Assays Aren’t a Big Pain with the Raptor Biphenyl LC Column • 231 compounds, 40+ isobars, 10 drug classes, 22 ESI- compounds in 10 minutes with 1 column. • A Raptor SPP LC column with time-tested Restek Biphenyl selectivity is the most versatile, multiclass-capable LC column available. • Achieve excellent separation of critical isobars with no tailing peaks. • Run fast and reliable high-throughput LC-MS/MS analyses with increased sensitivity using simple mobile phases. The use of pain management drugs is steadily increasing. As a result, hospital and reference labs are seeing an increase in patient samples that must be screened for a wide variety of pain management drugs to prevent drug abuse and to ensure patient safety and adherence to their medication regimen. Thera- peutic drug monitoring can be challenging due to the low cutoff levels, potential matrix interferences, and isobaric drug compounds. To address these chal- lenges, many drug testing facilities are turning to liquid chromatography coupled with mass spectrometry (LC-MS/MS) for its increased speed, sensitivity, and specificity. As shown in the analysis below, Restek’s Raptor Biphenyl column is ideal for developing successful LC-MS/MS pain medication screening methodologies. With its exceptionally high retention and unique selectivity, 231 multiclass drug compounds and metabolites—including over 40 isobars—can be analyzed in just 10 minutes. In addition, separate panels have been optimized on the Raptor Biphenyl column specifically for opioids, antianxiety drugs, barbiturates, NSAIDs and analgesics, antidepressants, antiepileptics, antipsychotics, hallucinogens, and stimulants for use during confirmation and quantitative analyses.
    [Show full text]
  • Hypokalemic Periodic Paralysis - an Owner's Manual
    Hypokalemic periodic paralysis - an owner's manual Michael M. Segal MD PhD1, Karin Jurkat-Rott MD PhD2, Jacob Levitt MD3, Frank Lehmann-Horn MD PhD2 1 SimulConsult Inc., USA 2 University of Ulm, Germany 3 Mt. Sinai Medical Center, New York, USA 5 June 2009 This article focuses on questions that arise about diagnosis and treatment for people with hypokalemic periodic paralysis. We will focus on the familial form of hypokalemic periodic paralysis that is due to mutations in one of various genes for ion channels. We will only briefly mention other �secondary� forms such as those due to hormone abnormalities or due to kidney disorders that result in chronically low potassium levels in the blood. One can be the only one in a family known to have familial hypokalemic periodic paralysis if there has been a new mutation or if others in the family are not aware of their illness. For more general background about hypokalemic periodic paralysis, a variety of descriptions of the disease are available, aimed at physicians or patients. Diagnosis What tests are used to diagnose hypokalemic periodic paralysis? The best tests to diagnose hypokalemic periodic paralysis are measuring the blood potassium level during an attack of paralysis and checking for known gene mutations. Other tests sometimes used in diagnosing periodic paralysis patients are the Compound Muscle Action Potential (CMAP) and Exercise EMG; further details are here. The most definitive way to make the diagnosis is to identify one of the calcium channel gene mutations or sodium channel gene mutations known to cause the disease. However, known mutations are found in only 70% of people with hypokalemic periodic paralysis (60% have known calcium channel mutations and 10% have known sodium channel mutations).
    [Show full text]