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Identification of Channels Underlying the M-Like Potassium Current In Identification of channeis underiying the M-like potassium current in NG108-15 neurobiastoma-giioma ceiis A thesis submitted for the degree of Doctor of Philosophy University of London by Jennifer Kathleen Hadley Department of Pharmacology University College London Gower Street London WC1E 6BT ProQuest Number: U644085 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 U644085 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 NG108-15 cells express a potassium current resembling the IVI-current found in sympathetic ganglia. I contributed to the identification of the channels underlying this NG108-15 current. I used patch-clamp methodology to characterise the kinetics and pharmacology of the M-like current and of three candidate channel genes, all capable of producing “delayed rectifier” currents, expressed in mammalian cells. I studied two Kvi .2 clones: NGK1 (rat Kvi .2) expressed in mouse fibroblasts, and MK2 (mouse brain Kvi .2) expressed in Chinese hamster ovary (OHO) cells. Kvi.2 showed relatively positive activation that shifted negatively on repeated activation, some inactivation, block by dendrotoxin and various cations, and activation by niflumic acid. It had persuasive differences from the M-like current. mErg is the mouse homologue of the cardiac ether-a-go-go-related gene channel HERG. Having discovered that the HERG blocker WAY-123,398 partially inhibited the M-like current, I studied mErgla in OHO cells. mErg la , as previously reported, undergoes intense inactivation, removed on hyperpolarisation to give a transient increase in current preceding deactivation. I report that it can also produce a sustained current with kinetic and pharmacological correspondences to the slow component of the M-like current. Blocking the presumed mErg component in NG108-15 left a current very similar to the sympathetic ganglion M-current. The latter was recently suggested to comprise a heteromultimer of KCNQ2 and KCNQ3, two neuronal relatives of the cardiac KvLQT 1. I expressed KCNQ2 and KCNQ3 in CHO cells, separately and together. Their kinetics match those of the M-current. The M-current blocker linopirdine blocks these channels indiscriminately, while tetraethylammonium blocks KGNQ2 > KCNQ2/KCNQ3 > KCNQ3. Since the selective blockers linopirdine and WAY-123,398, applied together, eliminate the total M-like current, Kvi .2 and other channels are unlikely to contribute. I conclude that blockers, when backed up by kinetic and expression data, were a particularly valuable tool for identifying M-like current components. Table of contents Title...........................................................................................................................................................1 Abstract...................................................................................................................................................2 Table of contents................................................................................................................................... 3 Additional material not bound in.......................................................................................................... 6 List of figures.......................................................................................................................................... 6 List of tables........................................................................................................................................... 7 List of abbreviations and constants.....................................................................................................8 Nomenclature and homologues of potassium channels..................................................................9 Acknowledgements............................................................................................................................. 10 Preface: the M-current.........................................................................................................................11 Chapter 1 : Introduction - Sympathetic M-currents and the M-like current in NG108-15 cells. 1 2 Background to the M-current......................................................................................................... 12 Discovery of the M-current..............................................................................................................13 Properties of the M-current in sympathetic cells........................................................................ 13 The NG108-15 neuroblastoma-glioma hybrid line ...................................................................... 14 Properties of the NG108-15 M-like current.................................................................................. 15 Pharmacology: potassium channei blockers suggest heterogeneity of “M-currents”........... 18 Receptor effects on the M-like current..........................................................................................18 Potassium channels in the cloning era.........................................................................................19 Molecular identification of M- and M-like channels.....................................................................22 My work............................................................................................................................................ 22 Chapter 2: Methods.............................................................................................................................23 Cell culture........................................................................................................................................23 T ransfection......................................................................................................................................24 Electrophysiology .............................................................................................................................25 Patch pipettes.................................................................................................................................. 25 Considerations relating to internal solutions................................................................................25 Compositions of internal solutions................................................................................................ 27 Drug addition................................................................................................................................... 28 Hardware and software...................................................................................................................28 Electrodes.........................................................................................................................................28 Instrumentation: (1) Axoclamp-2.................................................................................................. 29 Recording procedure with the Axoclamp-2.................................................................................29 Instrumentation: (2) Axopatch-200 recordingprocedure ............................................................ 30 Compensation of series resistance..............................................................................................31 Analysis ............................................................................................................................................33 Leak-subtraction of data records.................................................................................................. 33 Fitting deactivation tails..................................................................................................................33 More detail on fitting equations......................................................................................................35 Chemicals.........................................................................................................................................36 Stably transfected cell lines and clones....................................................................................... 36 Chapter 3: Kvi .2 .................................................................................................................................37 3.1 : Kvi .2 - a candidate for the M-iike current?......................................................................... 37 Sites of expression of Kvi .2..........................................................................................................37 NG108-15 ceiis: NGK1 and NGK2 ...............................................................................................38 Kinetics of Kvi .2..............................................................................................................................38 Potassium channel blockers acting on Kvi .2............................................................................. 39 Neurotransmitter modulation
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