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Ca2+ Signaling in Porcine Myometrial Cells: Ca2+ Channels, Intracellular Ca2+ Stores and Guanine Nucleotide-Binding Protein-Coup

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Ca2+ Signaling in Porcine Myometrial Cells: Ca2+ Channels, Intracellular Ca2+ Stores and Guanine Nucleotide-Binding Protein-Coup Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1995 Ca2+ signaling in porcine myometrial cells: Ca2+ channels, intracellular Ca2+ stores and guanine nucleotide-binding protein-coupled receptors Ronghua ZhuGe Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Animal Sciences Commons, Cell Biology Commons, Veterinary Physiology Commons, and the Veterinary Toxicology and Pharmacology Commons Recommended Citation ZhuGe, Ronghua, "Ca2+ signaling in porcine myometrial cells: Ca2+ channels, intracellular Ca2+ stores and guanine nucleotide- binding protein-coupled receptors " (1995). Retrospective Theses and Dissertations. 11026. https://lib.dr.iastate.edu/rtd/11026 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reprodaction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and in^roper alignment can adversely affect reproductioiL In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note win indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing firom left to r^t in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photogr^hs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for ai^ photographs or illustrations q)pearing in this copy for an additional charge. Contact UMI directly to order. A Bell & Howell Information Company 300 North ZeebRoad. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800/521-0600 signaling in porcine myometrial cells: Ca^"^ channels, intracellular Ca^^ stores and guanine nucleotide-binding protein-coupled receptors by Ronghua ZhuGe A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment of the Requirement for the Degree of DOCTOR OF PHILOSOPHY Department: Veterinary Physiology and Pharmacology Major: Physiology (Pharmacology) Approved: Signature was redacted for privacy. In Ciharge of M^jor Work Signature was redacted for privacy. For the Major Department Signature was redacted for privacy. For the Graduate College Iowa State University Ames, Iowa 1995 UMI Number; 9606633 UMI Microform 9606633 Copyright 1995, by DM1 Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 1 Ca^"^ signaling in porcine myometrial cells: Ca^"^ channels, intracellular Ca^^ stores and guanine nucleotide-binding protein (G protein)-coupled receptors Ronghua ZhuGe Major professor: Walter H. Hsu Iowa State University Fura-2 spectrofluorometry and imaging, and whole-cell patch-clamp techniques were used to characterize channels and intracellular Ca^^ stores for exploring signal transduction of the oxytocin receptor and the a2A-adrenergic receptor in freshly dispersed porcine myometrial cells. Two types of voltage-dependent Ca^^ channels, i.e., L-type and T-type, were found in 8% of myometrial cells while in 92% of the cells, only L-type Ca^^ channels were detected. The analysis of occurrence, voltage dependence and kinetics of Ca^"^ channels suggested that L-type channels were responsible for the delivery of Ca^^ into cell upon membrane depolarization and T-type channel may be involved in uterine pacemaking. In addition to the Insd ,4,5)P3- sensitive Ca^"^ store, the myometrial cells contained the caffeine- and ryanodine- sensitive store. release from the caffeine- and ryanodine-sensitive store in a fashion of quanta, in which quanta was defined as part of stores in 70% and the entire stores in 30% of cells. Activation of oxytocin receptors and OjA'aclrenergic receptors induced an increase in the intracellular Ca^"^ concentration ([Ca^^],) through release from intracellular stores and influx from extracellular environment. The contribution of influx and release was variable between two receptors: the release was a predominate component for oxytocin receptors while the influx is the major one for OjA-adrenergic receptors. The release process posed by activation of oxytocin receptors and OjA-adrenergic receptors was mediated by activation of lns(1,4,5)P3 receptors via a pertussis toxin (PTX)-insensitive G protein-phospholipase C-lns (1,4,5)P3 cascade. Oxytocin receptor-mediated influx was predominately attributed to opening of receptor-operated Ca^"^ channels, and to a lesser extent by L-type channels. The capacitative Ca^"^ entry mechanism could not account for activation of these channels, instead, it required a concomitant formation of lns(1,4,5)P3 and depletion of 2 Ca^"^ stores. On the other hand, the depletion of Ca^^ stores was not involved in CTja" adrenergic receptor-induced Ca^^ influx. Instead this influx was primarily mediated by opening of L-type Ca^"^ channels which resulted from a decrease in cAMP through a PTX-sensitive G protein-adenlylyl cyclase mechanism, or a direct coupling of the channels with a PTX-sensitive G protein. ii TABLE OF CONTENTS LIST OF ABBREVIATIONS v CHAPTER I GENERAL INTRODUCTION 1 Dissertation Organization 1 Research Objective 1 Background and Literature Review 3 CHAPTER II RATIONALE 32 CHAPTER III CHARACTERIZATION OF FRESHLY DISPERSED PORCINE 36 MYOMETRIAL CELLS: EVIDENCE FOR VOLTAGE-DEPENDENT CA^"" CHANNEL AND REGULATORY RECEPTORS Introduction 37 Materials and Methods 38 Results 41 Discussion 51 References 53 CHAPTER IV ROLES OF TWO TYPES OF CALCIUM CHANNELS IN MYOMETRIAL 57 CELLS FROM PREPARTUM SOWS Summary 57 Introduction 58 Materials and Methods 59 Results 61 Discussion 78 Acknowledgements 86 References 86 CHAPTER V CAFFEINE-AND RYANODINE-SENSITIVE STORES IN PORCINE 91 MYOMETRIAL CELLS: HETEROGENEITY OF ALL-OR-NONE CALCIUM RELEASE Abstract 91 Introduction 92 iii Metiiods 94 Results 95 Discussion 105 Acknowledgments 112 References 11 2 CHAPTER VI OXYTOCIN-INDUCED A BIPHASIC INCREASE IN [CA'^], IN 117 PORCINE MYOMETRIAL CELLS FROM PREPARTUM SOWS: PARTICIPATION OF PERTUSSIS-SENSITIVE G-PROTEIN, INOSITOL-1,4,5-TRISPHOSPHATE- SENSITIVE CA^-" STORE AND VOLTAGE-DEPENDENT CA'^" CHANNELS Abstract 11 7 Introduction 118 Materials and Methods 11 9 Results 122 Discussion 137 Acknowledgements 141 References 141 CHAPTER VII SIGNALING MECHANISMS ON Oj-ADRENERGIC RECEPTOR- 146 MEDIATED CA^"' INFLUX AND RELEASE IN PORCINE MYOMETRIAL CELLS Abstract 146 Introduction 147 Experimental Procedures 148 Results 150 Discussion 165 Acknowledgments 172 References 172 CHAPTER Vlil GENERAL DISCUSSION 175 L-type and T-type Voltage-dependent Ca^"^ Channels 175 IP3- and Caffeine-sensitive intracellular Ca^^ Stores 177 Modulation of L-type Ca^^ Currents by G Protein-coupled Receptors 179 Voltage-independent Ca^"^ Channels 181 iv Modulation of Ca^^ by G protein-coupled Receptors 182 G protein: Signal Organizer 183 Physiological Implications of Oj-adrenergic receptors 184 CHAPTER IX GENERAL CONCLUSIONS 187 LITERATURE CITED 191 ACKNOWLEDGEMENTS 210 V LIST OF ABBREVIATIONS AR adrenergic receptor CaM calmodulin DHP dihydropyridine EGTA [ethylenebis (oxyethylenenitrilo)] tetraacetic acid Epi epinephrine Fura-2 AM fura-2 acetoxymethi ester G protein guanine nucleotide-binding protein HBSS Hank's balanced salt solution HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid 1 current Ica Ca^^ current iga Ba^"^ current IP3 Inositol 1,4,5-trisphosphate/Ca^'^-releasing channel IP3R inositol 1,4,5-trisphosphate receptor KRB Krebs-Ringer bicarbonate solution MLC nnyosin light chain MLCK myosin light chain kinase MLCP myosin light chain phosphatase OT oxytocin PG prostaglandin PKA cAMP-dependent protein kinase PKG cGMP-dependent protein kinase PLC phospholipase C PTX pertussis toxin ROC receptor-operated Ca^^ channel RyR ryanodine receptor/Ca^"^-releasing channel SR sarcoplasmic reticulum TG thapsigargin V potential or voltage VDCC voltage-dependent Ca^^ channel vi extracellular Ca^"^ concentration ICa^"^], intracellular Ca^"^ concentration CICR Ca^'^-induced Ca^^ influx 1 CHAPTER I GENERAL INTRODUCTION Dissertation Organization This dissertation contains five research papers preceded by a general introduction and a rationale, and followed by a general discussion, a summary and a list of references cited in the general introduction and discussion. The general introduction includes a research objective and a background and literature review. Chapters I and IV represent two papers previously published, and Chapters II, III and V correspond to manuscripts submitted for publication in American Journal of Physiology, the Journal
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