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Enac Regulation in the Kidney: the Role of Ankyrin G

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Enac Regulation in the Kidney: the Role of Ankyrin G ENAC REGULATION IN THE KIDNEY: THE ROLE OF ANKYRIN G by Christine A. Klemens B.S. University of Wisconsin, 2005 Submitted to the Graduate Faculty of The School of Medicine in partial fulfillment Of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2017 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Christine A. Klemens It was defended on April 11, 2017 and approved by Michael B. Butterworth, Ph.D., Assistant Professor, Cell Biology Daniel C. Devor, Ph.D., Professor, Cell Biology Donald B. DeFranco, Ph.D., Professor, Pharmacology and Chemical Biology Adam V. Kwiatkowski, Ph.D., Assistant Professor, Cell Biology Dissertation Director: Thomas R. Kleyman, M.D., Professor, Cell Biology ii Copyright © by Christine A. Klemens 2017 iii ENAC REGULATION IN THE KIDNEY THE ROLE OF ANKYRIN G Christine A. Klemens, Ph.D. University of Pittsburgh, 2017 The epithelial sodium channel (ENaC) is the limiting entry point for Na+ reabsorption in the distal kidney nephron and is regulated by numerous hormones, including the mineralocorticoid hormone aldosterone. Previously we identified ankyrin G (AnkG), a cytoskeletal protein involved in vesicular transport, as a novel aldosterone-induced protein that can alter Na+ transport in mouse cortical collecting duct cells. AnkG is highly expressed in the kidney, particularly in the distal nephron. Increasing AnkG expression increases ENaC activity while depleting AnkG reduces ENaC-mediated Na+ transport. The underlying mechanism presiding over this effect; however, was unknown. Here we report that AnkG expression directly regulates Na+ transport by altering ENaC activity in the apical membrane. These changes are due to a change in ENaC directly rather than through alterations to the Na+ driving force created by Na+K+ATPase. Using a constitutively open mutant of ENaC and surface biotinylation, we demonstrate that the augmentation of Na+ transport is caused predominantly by increasing the number of ENaCs at the surface rather than alterations to open probability. To determine the mechanism of AnkG action on ENaC surface number, changes in rates of internalization, recycling, and membrane delivery were investigated. AnkG did not alter ENaC delivery to the membrane from biosynthetic pathways or removal by endocytosis; however, AnkG did alter ENaC insertion from constitutive recycling pathways. We also investigated the potential role of a putative AnkG binding domain in the C-terminus of βENaC, and whether single-site mutations of a charged residue and two regulatory phosphorylation sites could disrupt AnkG augmentation of ENaC current. We did not find any significant evidence that this region is essential for AnkG-ENaC interaction. These findings iv provide a mechanism to account for the role of AnkG in the regulation of Na+ transport in the distal kidney nephron. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XIII 1.0 INTRODUCTION ........................................................................................................ 1 1.1 KIDNEY PHYSIOLOGY ................................................................................... 1 1.1.1 Glomerulus and Bowman’s Capsule .............................................................. 2 1.1.2 Proximal Tubule .............................................................................................. 3 1.1.3 Loop of Henle ................................................................................................... 3 1.1.4 Macula Densa ................................................................................................... 4 1.1.5 Distal Convoluted Tubule ............................................................................... 5 1.1.6 Collecting Duct ................................................................................................. 6 1.1.6.1 Transport in Intercalated Cells ........................................................... 7 1.1.6.2 Transport in Principal Cells................................................................. 7 1.1.7 Renin-Angiotensin-Aldosterone-System ........................................................ 8 1.1.7.1 Non-genomic Regulation of Aldosterone via miRNAs..................... 11 1.2 EPITHELIAL SODIUM CHANNEL .............................................................. 12 1.2.1 ENaC and Disease .......................................................................................... 12 1.2.2 ENaC Biophysical Properties ....................................................................... 13 1.2.3 ENaC Subunit Structure ............................................................................... 14 1.2.4 Cytoplasmic Domains .................................................................................... 15 1.2.4.1 Ubiquitination of ENaC ...................................................................... 16 1.2.4.2 Phosphorylation Events and ENaC Function ................................... 17 1.2.4.3 The Impact of Palmitoylation on ENaC Subunits............................ 19 vi 1.2.4.4 Cytoskeletal Interactions and ENaC ................................................. 19 1.2.5 Transmembrane Domains ............................................................................ 21 1.2.6 Extracellular Domains .................................................................................. 22 1.2.6.1 Proteolytic Cleavage and ENaC Activation ...................................... 22 1.2.6.2 Na+ Feed-back Inhibition and Self-Inhibition .................................. 23 1.2.6.3 Mechanosensing .................................................................................. 24 1.2.7 ENaC Proteostasis And Trafficking ............................................................ 25 1.3 NA+K+-ATPASE IN THE KIDNEY ................................................................ 29 1.4 ANKYRINS ........................................................................................................ 31 1.4.1 Discovery of Ankyrins ................................................................................... 31 1.4.2 Ankyrins and Disease .................................................................................... 32 1.4.2.1 Hereditary Spherocytosis ................................................................... 33 1.4.2.2 Ankyrin B Syndrome .......................................................................... 33 1.4.2.3 CRASH Syndrome .............................................................................. 34 1.4.2.4 AnkB, KATP, and glucose homeostasis ............................................... 34 1.4.2.5 Bipolar Disorder .................................................................................. 35 1.4.2.6 Brugada Syndome ............................................................................... 36 1.4.3 Ankyrin Domains ........................................................................................... 36 1.4.3.1 Membrane Binding Domain ............................................................... 37 1.4.3.2 Spectrin Binding Domain ................................................................... 38 1.4.3.3 Death Domain ...................................................................................... 39 1.4.3.4 C-terminal Domain ............................................................................. 40 1.4.4 Ankyrin Isoforms ........................................................................................... 43 vii 1.4.4.1 Canonical ankyrins (180-220 kDa) .................................................... 43 1.4.4.2 Small ankyrins (20-120 kDa) .............................................................. 44 1.4.4.3 Large ankyrins (270-480 kDa) ........................................................... 45 1.4.5 Ankyrin Function .......................................................................................... 46 1.4.6 Ankyrins in Epithelia .................................................................................... 47 1.4.6.1 Ankyrin and NKA ............................................................................... 47 1.4.6.2 Ankyrin and the Ammonium Transporter RhBG ........................... 51 1.4.6.3 Ankyrin and E-Cadherin ................................................................... 51 1.4.6.4 Ankyrin and ENaC ............................................................................. 53 1.4.7 Hypothesis ...................................................................................................... 54 2.0 RESULTS ................................................................................................................... 56 2.1 INTRODUCTION - MECHANISM OF ANKG-ENAC INTERACTION .. 56 2.1.1 AnkG is expressed in the kidney in the PT, TAL, DCT, and CD ............. 57 2.1.2 AnkG is expressed at the plasma membrane in mCCD cells .................... 59 2.1.3 Low Na+ diets do not detectably impact AnkG expression in mouse collecting ducts ........................................................................................................... 61 2.1.4 Variable Na+ diets do not change AnkG expression in rat kidneys at either the whole kidney level or in CDs ............................................................................... 63 2.1.5 AnkG expression alters vectorial Na+ transport ......................................... 64 2.1.6 Na+K+-ATPase (NKA) localization is unaffected
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