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Mechanisms Underlying Kcnq1channel Cell Volume Sensitivity

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Mechanisms Underlying Kcnq1channel Cell Volume Sensitivity THE PHD SCHOOL OF SC IENCE FACULTY OF SCIENCE UNIVERSITY OF COPENHAGEN PhD thesis Sofia Hammami Mechanisms underlying KCNQ1channel cell volume sensitivity Submitted: 10/05/10 1 TABLE OF CONTENTS Preface ............................................................................................................................................................... 5 Acknowledgements.......................................................................................................................................... 5 Publications ....................................................................................................................................................... 6 Summary ............................................................................................................................................................ 7 Dansk resumé ................................................................................................................................................... 8 Abbreviations ................................................................................................................................................... 9 Table of figures .............................................................................................................................................. 10 BACKGROUND .............................................................................................................................. 11 Ion Channels ................................................................................................................................................... 11 Mechanosensitive ion channels ................................................................................................................... 12 Cell volume sensitive ion channels .................................................................................................... 17 The KCNQ1 channel ........................................................................................................................... 18 1. Expression and role in epithelia and cardiac tissue ........................................................... 19 2. Regulation ................................................................................................................................ 20 a. Regulation by β subunits ................................................................................................... 21 b. Regulation by cell volume ................................................................................................. 23 Role of volume sensitive KCNQ1 in mammary epithelium ............................................ 23 Role of volume sensitive KCNQ1 in liver cells ................................................................. 24 Role of volume sensitive KCNQ1 in cardiomyocytes ...................................................... 24 Purinergic receptors and ATP signalling .................................................................................................... 25 Receptors .................................................................................................................................................... 25 ATP release mechanisms ......................................................................................................................... 26 THESIS OBJECTIVES .................................................................................................................... 28 METHODS ........................................................................................................................................ 29 Two-Electrode voltage clamp technique (TEVC) .................................................................................... 29 The patch clamp technique .......................................................................................................................... 30 ATP bioluminescent assay ............................................................................................................................ 30 Enzyme linked immunoassay for surface expression .............................................................................. 31 RESULTS AND DISCUSSION ..................................................................................................... 32 Cell swelling vs. membrane stretch ............................................................................................................. 33 ATP release and cell volume changes ......................................................................................................... 35 KCNQ1 association with KCNE1 and volume sensitivity ..................................................................... 36 The cytoskeleton ............................................................................................................................................ 38 Intracellular calcium ...................................................................................................................................... 38 Cytosolic pH ................................................................................................................................................... 38 Membrane PIP2 .............................................................................................................................................. 39 Kinases ............................................................................................................................................................. 39 Specific residues for the volume sensitive potassium channels .............................................................. 40 CONCLUSION ................................................................................................................................. 42 REFERENCE LIST ......................................................................................................................... 43 APPENDIX ....................................................................................................................................... 56 Manuscript I: Cell volume and membrane stretch independently control K + channel activity .................................................................................................................... 57 Manuscript II: KCNQ1 channel response to cell volume changes is not mediated by ATP release..................................................................................................................... 64 Manuscript III: KCNE1-induced increase in KCNQ1 currents is not mediated through enhanced plasma membrane expression .......................................................... 86 Related paper: Cell swelling and membrane stretch – A common trigger of potassium channel activation? ....................................................................................... 105 PhD thesis Sofia Hammami Preface This presented PhD thesis is the result of three years of work under supervision of Associate Prof. Niels J. Willumsen and Prof. Ivana Novak at the Department of Biology as well as Prof. Dan A. Klærke from the Department of Physiology and Biochemistry, IBHV, at LIFE. This thesis starts with a general introduction to ion channels followed by an overview of mechanosensitive ion channels with emphasis on volume sensitive potassium channels. Subsequently, I give a description of the KCNQ1 channel and how it is regulated by KCNE1 and by cell volume. This is followed by a brief description of purinergic receptors and ATP signalling. The basics of the different techniques used are described in the method section. Attached to the thesis, are one published article and two other submitted manuscripts. In the discussion, the main findings from these studies are briefly discussed and other possible mechanisms will also be included. In addition, I have attempted to propose different perspectives related to the further identification of the so far unknown mechanisms behind channel activation upon small, fast changes in cell volume. Acknowledgements Many people are deserving acknowledgement at this time for their help in making this project possible. First and foremost, I would like to thank my supervisors, Niels and Dan, for excellent guidance and continuous support. It has been a great pleasure to be under their wings during my master and PhD for almost 5 years. I also owe a great thank to Prof. Ivana Novak for the kind supervision and support I received from her during the last 1½ year of my work. I would like to thank all people from the 3rd floor at August Krogh building for a great working environment as well all the members of Dan Klærkes lab, former as well new members. A special thank goes to Zaida Rasmussen for technical help and support. Last, but not least, I‟m thankful to my family, friends and especially Martin for giving me moral support and for always being there when I needed him. 5 PhD thesis Sofia Hammami Publications My work as a PhD student has resulted in 1 published manuscript, 3 published abstracts and 2 submitted manuscripts. Additionally I was invited to write a short review article related to my first manuscript to be published in Physiology News magazine. 1 published article, 2 manuscripts and the related review article are included in the thesis (attached in Appendix): I. Hammami S, Willumsen NJ, Olsen HL, Morera FJ, Latorre R, & Klaerke DA (2009). Cell volume and membrane stretch independently control K+ channel activity. J Physiol 587, 2225-2231. II.
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