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Effects of Some Agents on Receptor-And Cell Volume-Controlled

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Effects of Some Agents on Receptor-And Cell Volume-Controlled EFFECTS OF SOME AGENTS ON RECEPTOR- AND CELL VOLUME- CONTROLLED CHANGES IN THE IONIC PERMEABILITY OF ISOLATED GUINEA-PIG HEPATOCYTES Christine A. Sandford A thesis submitted for the degree of Doctor of Phiiosophy. Department of Pharmacology University College London Gower Street LONDON WC1E 6BT 1992 ProQuest Number: 10017717 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10017717 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT Sodium-linked amino acid transport causes an increase in the membrane permeability of liver cells to potassium. This effect on permeability is generally attributed to the concomitant rise in cell volume produced by the inward movement of solute. It is thought to form the basis of the subsequent regulatory volume decrease. The first part of this study examined the pharmacology and electrical characteristics of cell volume regulation In isolated guinea-pig hepatocytes using intracellular recording techniques and the whole cell variant of the patch clamp technique. In patch clamp studies, cell swelling was induced by the application of hydrostatic pressure to the shank of the patch pipette. This produced a large outward K+ current in voltage clamped cells, apparently without a rise in cytosolic free Ca=+ concentration. Spectral analysis of the current noise during this response suggested that the K+ channel involved has a unitary conductance of 7pS. In microelectrode recordings, the volume activated potassium conductance (Gy) is sometimes triggered as a consequence of electrolyte leakage from the electrode and the influx of osmotically obliged water. This experimental artefact was turned to advantage in the current study to test the ability of a variety of agents to inhibit Gy. Gy demonstrated a similar sensitivity to cetiedil to the potassium conductances that subserve the Gardos effect in red blood cells and the volume regulatory decrease described in lymphocytes subjected to hypotonic stress. Its insensitivity to oligomycin A and oxpentifylline, however, sets Gy apart from these cetiedil sensitive conductances. The second part of this study looks at various aspects of the hormonal regulation of liver cell membrane permeability. The changes in membrane conductance evoked by Pg-purinoceptor activation were 1 investigated first. Previous workers have demonstrated that Ca=+ mobilizing agonists trigger Ca^+-actlvated K+ and c r permeabilities (PK(Ca) and Pci(Ca)) in the liver. In the present study, it was shown that whereas low concentrations of ATP exclusively activate the Ca^+-gated K and Cl channels, larger concentrations also induce a transient depolarizing current which flows through a separate conductive pathway that does not depend on intraceliular Ca^*. The mechanisms coupling hormonal receptor stimulation to the activation of P K (C a) and P c i(C a ) were addressed next. Fast oscillations in membrane conductance were observed when the hepatocytes were stimulated by submaximal concentrations of either the Ca7+ mobilizing agonist ATP or the cAMP-dependent agonist salbutamoi. The cellular basis for this oscillatory activity was explored by employing the whole cell patch technique to introduce the putative second messengers cAMP and inositol 1,4,5 trisphosphate (IP3) into the cells. The results obtained suggest the release of intracellular Ca^'*’ by both cAMP and IP3 can be pulsatile. Finally, the potentiating effect of salbutamoi on the membrane response to ATP, described previously in liver slices and cell suspensions, was re-examined at the singie cell level. The dose-response relationship of single cells to ATP was found to shift to the left in the presence of salbutamoi, so that near threshold concentrations of this agonist became sufficient in some cells to set in motion the series of cyclical fluctuations In cytosolic calcium, normally associated with more intense stimulation. These results are discussed in the context of Berridge’s two pool model of intracellular calcium homeostasis. CONTENTS Page ABSTRACT: 1 INDEX: 3 FIGURES: 8 TABLES: 11 PUBLICATIONS: 12 ACKNOWLEDGEMENTS: 13 CHAPTER 1. INTRODUCTION 1.1 Introduction ........................................................................................................ 14 1.2 The liver............................................................................................................... 15 1.2.1 The physiological functions of the liver ........................................... 15 1.2.2 The histological organisation of the liver: the lobule 17 1.2.3 The innervation of the liver...................................................................... 19 1.2.3.1 The function of hepatic nerves................................................................. 20 1.3 The suitability of the isolated liver cell as an experimental m a te ria l................................................................................................................ 21 1.3.1 The polarity of the isolated cell .......................................................... 21 1.3.2 The ion d is trib u tio n across the c e ll membrane measured in vivo and in v itro...................................................................................... 23 1.3.3 The membrane potential of liver cells in vivo ar\6 in v itro................................................................................................................ 25 1.4 Can the Goldman constant field equation adequately describe the resting membrane potential of the liver cell?...................... 27 1.5 The relationship between membrane permeability and cell volume.................................................................................................................... 30 Page 1.5.1 A role for in the volume-activated increase in potassium permeability ....................................................................................................... 31 1.6 The influence of hormones on ion movements...................................... 32 1.6.1 The involvement of Ca^'*’ in hormone mediated changes in liver membrane p e rm e a b ility ...................................................................... 33 1.6.2 The association between receptor occupation and PI turnover.............................................................................................................. 36 1.6.3 IP 3 - a second messenger fo r Ca^^ m o b iliz a tio n............................ 37 1.6.4 The hormone se n s itiv e Ca^'*’ pool............................................................ 38 1.6.4.1 Does the IP3 insensitive pool contribute to Ca^"*’ signal initiated by Ins( 1 , 4 , 5 )P 3......................................................................... 40 1.6.5 The mobilization of intracellular 03^+ by In s ( 1 , 4 , 5 )P 3 .......... 40 1.6.5.1 The mobilization of intracellular 03 %+ by cAMP ............................ 42 1.6.6 The mobilization of extracellular Ca^*............................................. 42 1.7 The aims of the present study................................................................. 44 CHAPTER 2. MATERIALS & METHODS 2.1 Preparation of isolated hepatocytes.................................................... 47 2.1.1 Hepatocyte isolation ..................................................................................... 47 2.1.2 S o lutio ns............................................................................................................. 48 2.1.3 Viability of cells ......................................................................................... 50 2.2 Short term culture of hepatocytes........................................................ 50 2.3 Intracellular recording from hepatocytes......................................... 51 2.3.1 Recording medium............................................................................................. 51 2.3.2 Recording conditions.................................................................................... 51 2.3.3 Microelectrodes............................................................................................... 52 Page 2.3.4 The measurement o f membrane p o te n tia l and input resistance using a single microelectrode................................................................ 53 2.4 Whole c e ll patch clamp recording............................................... 53 2.4.1 E x tra c e llu la r medium..................................................................................... 53 2.4.2 Recording conditions..................................................................................... 54 2.4.3 Patch pipettes.................................................................................................. 54 2.4.4 Whole cell recording from hepatocytes............................................... 55 2.4.5 Intracellular dialysis ................................................................................ 56 2.4.6 Changes in cell volume...............................................................................
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