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Conductance-Independent Intracellular Signaling Via the EAG

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Conductance-Independent Intracellular Signaling Via the EAG VOLTAGE-DEPENDENT REGULATION OF INTRACELLULAR SIGNALING BY ETHER À GO-GO K+ CHANNELS by Andrew Peter Hegle A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular, Cellular and Developmental Biology) in The University of Michigan 2007 Doctoral Committee: Assistant Professor Gisela Wilson, Co-Chair Professor Richard I. Hume, Co-Chair Associate Professor Cunming Duan Associate Professor Lori L. Isom Assistant Professor Mohammed Akaaboune Andrew Peter Hegle © 2007 All rights reserved To my extraordinary sister Alicia, in memory of our father Terry Dean Hegle ii ACKNOWLEDGEMENTS More than anyone, I would like to thank Angelique Pilon, my dearest love and best friend. I can’t imagine what these years would have been like without her in my life. I sincerely thank Gisela Wilson for her encouragement, patience and inspiration as a mentor. Her scientific insights and boundless optimism, as well as our conversations of politics, music and life will be greatly missed. I also thank the members of my thesis committee for their tremendous support and guidance, particularly Rich Hume, who has contributed immeasurably to my experience here. In addition, I owe a great deal of thanks to Laura Olsen, Jesse Hay and Rolf Bodmer for believing in me during my undergraduate years, and for motivating me to pursue a career in scientific research. I also thank Mary Carr, Diane Durfy and the rest of the MCDB administrative staff, whose incredible support and wonderful sense of humor have been essential to my graduate career. I wish to extend special thanks to my lab partner and colleague Dan Marble, who has been there with me every step of the way, and to all the others who have worked in the Wilson lab, including Eric Snyder II, Sarah Telfer, Katherine MacNair and Divya Sharma. I also thank Dylan Clyne, Louis Saint-Amant, David Parker, Tanya Johnson and Aaron Wyman for their sage advice and keen insights into graduate life over the years, and the rest of my fantastic third floor colleagues, in no particular order; Peter Schleuter, iii Sean Low, Mark Miller, Emile Bruneau, Eric Horstick, Shlomo Dellal, Rachel Tittle and Dani Brennan, for everything. Special thanks is also due to Jonathan Pan, who persuaded me long ago to sit in front, pay attention and believe in myself. Outside of MCDB, the rest of my family and friends have contributed greatly to my graduate experience. I especially thank my mother Janis and my sister Alicia for their unwavering love and support of all my endeavors. I am also indebted to the trust and guidance of my late father Terry, whose remarkable spirit I carry with me always, and to my late grandfather Alton Conklin, who taught me more during childhood than I ever realized. I also thank the Bosleys, Taglauers, Molyneauxs, and the rest of my incredible family for their patience, love and respect. Finally, I want to thank the friends that have been with me, through thick and thin, from the Batcave and beyond, who have made these years unforgettable: Seth Gordon, Chris Goretski, Eric Dyer, Alison Melnick, Sarah Shotwell, Dan Kruse, Jon Kraus, Jeremy Mogtader, Mike DeYounker, Jack Van Dyke, Bill Bon, Andy Harrington, Steve Gertz, Mike Kuhn, Jon Goldstein, James Olzmann, and so many others without which my life would not be the same. A special thanks is also due to my oldest friends, Ryan Norton, Eric Ososki and Mike Paulus, whose influences remain an essential element of my character. iv PREFACE Some data presented in this thesis have been previously published or are in preparation for publication at the time of this writing. Chapter II was published in 2006 in the Proceedings of the National Academy of Sciences of the United States of America (PNAS 103.8:2886-2891). Chapter III is in preparation for submission to Nature. These chapters were written collaboratively with my thesis advisor, Gisela F. Wilson. Although I performed most of the data analysis and writing, Gisela contributed to the physiological characterization of EAG mutant channels presented in these chapters, and was also very helpful in the editing of the entire thesis. Dan Marble generated the Drosophila transgenics and several of the EAG point mutants, with assistance from an exceptional undergraduate student, Katherine MacNair. Dan also characterized the larval mutant phenotypes and contributed to the editing of Chapters II and III. I am immensely appreciative of Dan and Gisela’s considerable contributions to this work, which would not have been possible without their efforts. The Appendix was published in 2005 in the Journal of Neuroscience (J. Neurosci. 25.20:4898-4907). I performed the immunocytochemical experiments and analysis presented in Figures A.3 and A.6, and also assisted with the editing of the paper, which was primarily written by Dan and Gisela. Eric Snyder, Spiros Dimitratos and Peter J. Bryant also contributed to the experimental results, and I thank them for their work. v TABLE OF CONTENTS DEDICATION…………………………………………………………………... ii ACKNOWLEDGEMENTS……………………………………………………. iii PREFACE ……………………………………………………………………….. v LIST OF FIGURES …………………………………………………………….. x ABSTRACT……………………………………………………………………..xii CHAPTER I. INTRODUCTION…………………………………………………...…...1 A. Thesis overview………………………………………………………...1 B. Background & significance of voltage-gated K+ channels……………. 4 C. Ion channels that influence the cell cycle…………………………….... 8 1. Proliferation in the immune system…………………………... 10 2. The role of K+ channels in cancer…………………………….. 13 3. Other channels involved in oncogenesis……………………… 17 4. Channel-mediated apoptosis and tumor suppression…………. 19 D. Non-conducting functions of ion channel proteins…………………... 22 1. TRP channels have intrinsic enzymatic activity……………… 23 2. K+ channels regulate homeostatic channel expression……….. 26 3. HCN channels are involved in synaptic facilitation………….. 28 vi 4. Ca2+ channels regulate muscle contraction and vesicle fusion.. 30 5. Other voltage-sensing proteins………………………………...33 E. Auxiliary subunits and ion channel signaling………………………... 35 1. Na+ channel β-subunits are cell adhesion proteins…………….36 2. K+ channel β-subunits have enzymatic activity………………. 38 3. Calmodulin-mediated channel signaling……………………… 46 4. Proteolysis of channels and subunits…………………………. 49 F. The EAG potassium channel…………………………………………. 53 1. Characterization and physiological significance……………... 54 2. Electrophysiological properties………………………………. 56 3. Topology and amino acid sequence…………………………... 59 4. The EAG protein complex……………………………………. 61 5. CaMKII activity is regulated by EAG………………………... 65 G. EAG regulates intracellular signaling pathways……………………... 66 II. A VOLTAGE-DRIVEN SWITCH FOR ION-INDEPENDENT SIGNALING BY ETHER À GO-GO K+ CHANNELS…………….... 70 A. Abstract………………………………………………………………. 70 B. Introduction…………………………………………………………... 71 C. Results……………………………………………………….……….. 72 D. Discussion………………………………………………………..…... 84 E. Materials & Methods……………………………………….………… 88 vii III. CONDUCTANCE-INDEPENDENT GATING OF CAMKII BY ETHER À GO-GO K+ CHANNELS……………………….……... 92 A. Abstract & Introduction……………………………………………… 92 B. Results……………………………………………………….……….. 93 C. Discussion……………………………………………………………108 D. Materials & Methods……………………………………….………..110 IV. DISCUSSION.……………………………………….………….…….. 115 A. Biophysical mechanisms of EAG signaling…………………………117 1. Kinetic models of EAG-regulated proliferation……………...118 2. EAG subunit stoichiometry………………………………….. 123 3. The link between CaMKII and voltage sensor……………….124 B. Cellular mechanisms of EAG signaling…………………….………. 129 1. Downstream targets of CaMKII……………………………... 131 2. Regulation of EAG surface expression by Camguk………… 132 3. Subcellular localization of EAG…………………………….. 135 C. Physiological significance of EAG signaling…………………..……137 1. Synaptic plasticity & homeostasis…………………………... 138 2. Cell cycle & oncogenesis……………………………………. 142 3. Final conclusions……………………………………………. 144 viii APPENDIX CAMGUK/CASK ENHANCES ETHER À GO-GO K+ CURRENT BY A PHOSPHORYLATION-DEPENDENT MECHANISM……. 146 A. Abstract……………………………………………………………... 146 B. Introduction…………………………………………………………. 147 C. Results……………………………………………………….……… 149 D. Discussion………………………………………………………..…. 171 E. Materials & Methods……………………………………….……….. 175 BIBLIOGRAPHY…………………………………………………………….. 184 ix LIST OF FIGURES CHAPTER I: INTRODUCTION Figure 1.1: EAG amino acid sequence………………………………..60 CHAPTER II: A VOLTAGE-DRIVEN SWITCH FOR ION-INDEPENDENT SIGNALING BY ETHER À GO-GO K+ CHANNELS Figure 2.1: EAG stimulates proliferation of NIH 3T3 fibroblasts…... 73 Figure 2.2: EAG-mediated signaling is independent of K+ conductance……………………………………………… 76 Figure 2.3: Comparison of the properties of wild type and mutant EAG channels…………………………………………… 81 Figure 2.4: EAG-mediated signaling is regulated by channel conformation…………………………………………….. 83 CHAPTER III: CONDUCTANCE-INDEPENDENT GATING OF CAMKII BY ETHER À GO-GO K+ CHANNELS Figure 3.1: CaMKII binding is essential for EAG signaling………… 96 Figure 3.2: EAG gating regulates membrane-associated CaMKII activity……………………………………………………99 Figure 3.3: CaMKII-dependent signaling is conserved in mammalian EAG………………………………………. 103 Figure 3.4: EAG signaling contributes to synaptic function in vivo………………………………………………….. 107 x CHAPTER IV: DISCUSSION Figure 4.1: Model of EAG/CaMKII signaling………………………141 APPENDIX: CAMGUK/CASK ENHANCES ETHER À GO-GO POTASSIUM CURRENT VIA A PHOSPHORYLATION- DEPENDENT MECHANISM Figure A.1: CMG increases EAG current and conductance.………...151 Figure A.2: CMG associates with EAG
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