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Modulation of Asic1a Function by Sigma-1 Receptors: Physiological and Pathophysiological Implications

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Modulation of Asic1a Function by Sigma-1 Receptors: Physiological and Pathophysiological Implications University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 2-27-2009 Modulation of ASIC1a Function by Sigma-1 Receptors: Physiological and Pathophysiological Implications Yelenis Herrera University of South Florida Follow this and additional works at: https://scholarcommons.usf.edu/etd Part of the American Studies Commons Scholar Commons Citation Herrera, Yelenis, "Modulation of ASIC1a Function by Sigma-1 Receptors: Physiological and Pathophysiological Implications" (2009). Graduate Theses and Dissertations. https://scholarcommons.usf.edu/etd/2011 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Modulation of ASIC1a Function by Sigma-1 Receptors: Physiological and Pathophysiological Implications by Yelenis Herrera A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences Department of Molecular Pharmacology and Physiology College of Medicine University of South Florida Major Professor: Javier Cuevas, Ph.D. Keith R. Pennypacker, Ph.D. Eric S. Bennett, Ph.D. Jay B. Dean, Ph.D. Alison Willing, Ph.D. ZhiGang Xiong, Ph.D. Date of Approval: February 27, 2009 Keywords: intracellular calcium, whole-cell currents, AKAP150, calcineurin, G protein, neurotransmission, glutamate, VGCC, NMDA receptor © Copyright 2009, Yelenis Herrera DEDICATION Those who have inspired me throughout my life and scientific career are those that I love the most. This dissertation is dedicated to them - my husband and family. I would like to thank my Mom and Dad for giving me the opportunity to be free, succeed and pursue my education. To my brother, you are the best and I am very proud of you; thank you for always being there and for your support. I would like to give a special thanks to my husband, Roger, for his love and always putting a smile in my face, and for his understanding, support and encouragement in making this dream possible. This accomplishment would have not been feasible if it was not for all of you. Thank you all and I love you all very much. I would also like to dedicate this thesis to my baby, Dukey. ACKNOWLEDGMENTS First of all, I would to thank my mentor, Dr. Javier Cuevas, for giving me the opportunity to grow as a scientist, for his support, inspiration and encouragement throughout the years. I would also like to thank my committee members, Drs. Keith R. Pennypacker, Eric S. Bennett, Jay B. Dean and Alison Willing, for their scientific advice and support. I would like to extend my gratitude to my external examiner, Dr. ZhiGang Xiong, for accepting to chair my dissertation committee and for his constructive comments on the dissertation. I would like to thank all the members of Dr. Cuevas’ laboratory, Dr. Christopher Katnik, Trimetria Bonds, Crystal Reed, Adam Behensky and Michelle Cortes-Salva, for their help and support all these years. Last but not least, I would like to thank the Chair, Dr. Bruce G. Lindsey, and staff, Bridget Shields and Barbara Nicholson, of the department of Molecular Pharmacology and Physiology for all their assistance. Thank you all very much. This work was funded in part by a McKnight Doctoral Fellowship from the Florida Education Fund. TABLE OF CONTENTS LIST OF FIGURES ............................................................................................... iii ABSTRACT ......................................................................................................... vii CHAPTER 1 INTRODUCTION ............................................................................. 1 Significance ....................................................................................................... 1 Background ....................................................................................................... 1 Pathobiology of Stroke ...................................................................................... 4 Acid-Sensing Ion Channels (ASIC) ................................................................... 8 ASIC1a Channels, Calcineurin and Scaffolding Proteins ................................ 13 Sigma Receptors ............................................................................................ 16 In Vitro Chemical Ischemia Models ................................................................. 22 CHAPTER 2 SIGMA-1 RECEPTOR MODULATION OF ASIC1a CHANNELS AND ASIC1a-INDUCED Ca2+ INFLUX IN RAT CORTICAL NEURONS.......................................................................................................... 25 Introduction ..................................................................................................... 25 Materials and Methods .................................................................................... 28 Primary Rat Cortical Neuron Preparation .................................................... 28 Calcium Imaging Measurements ................................................................. 29 Electrophysiology Recordings ..................................................................... 30 Solutions and Reagents .............................................................................. 31 Data Analysis .............................................................................................. 31 Results ............................................................................................................ 32 Discussion ....................................................................................................... 69 CHAPTER 3 SIGMA-1 RECEPTOR ACTIVATION INHIBITS ASIC1a CHANNELS VIA A PERTUSSIS TOXIN SENSITIVE G PROTEIN AND AN AKAP/CALCINEURIN COMPLEX ...................................................................... 75 Introduction ..................................................................................................... 75 Materials and Methods .................................................................................... 78 Primary Rat Cortical Neuron Preparation .................................................... 78 Calcium Imaging Measurements ................................................................. 78 Electrophysiology Recordings ..................................................................... 79 Immunohistochemistry................................................................................. 80 Confocal Microscopy ................................................................................... 81 Solutions and Reagents .............................................................................. 82 Data Analysis .............................................................................................. 82 i Results ............................................................................................................ 83 Discussion ..................................................................................................... 107 CHAPTER 4 SIGMA-1 RECEPTOR INHIBITION OF INTRACELLULAR Ca2+ DYSREGULATION DUE TO SYNERGISTIC INTERACTION BETWEEN ACIDOSIS AND ISCHEMIA ........................................................... 113 Introduction ................................................................................................... 113 Materials and Methods .................................................................................. 117 Primary Rat Cortical Neuron Preparation .................................................. 117 Calcium Imaging Measurements ............................................................... 117 Electrophysiology Recordings ................................................................... 118 Solutions and Reagents ............................................................................ 118 Data Analysis ............................................................................................ 119 Results .......................................................................................................... 120 Discussion ..................................................................................................... 150 CHAPTER 5 DISCUSSION .............................................................................. 159 Conclusions .................................................................................................. 159 Overall Significance ...................................................................................... 176 LIST OF REFERENCES .................................................................................. 184 APPENDICES .................................................................................................. 204 Appendix A – Pharmacological Compounds ................................................. 205 ABOUT THE AUTHOR ........................................................................... End Page ii LIST OF FIGURES Figure 1.1 Pathobiology of ischemic stroke.………………………………………7 2+ Figure 2.1 ASIC1a blockers inhibit proton-evoked increases in [Ca ]i in cultured cortical neurons from embryonic (E18) rats………………46 Figure 2.2 Pan-selective sigma agonists inhibit proton-evoked transient 2+ increases in [Ca ]i…………………………………………………….48 Figure 2.3 Activation of σ-1 receptors inhibits ASIC1a-induced increases in 2+ [Ca ]i……………………………………...…………………………....50 Figure 2.4 Inhibition of σ-1 receptors blocks CBP-mediated suppression
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