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PROPERTIES of DRUG BLOCKADE of a LARGE CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNEL in CULTURED RAT HIPPOCAMPAL NEURONS by XUEPING WANG M.D

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PROPERTIES of DRUG BLOCKADE of a LARGE CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNEL in CULTURED RAT HIPPOCAMPAL NEURONS by XUEPING WANG M.D PROPERTIES OF DRUG BLOCKADE OF A LARGE CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNEL IN CULTURED RAT HIPPOCAMPAL NEURONS by XUEPING WANG M.D. Beijing Medical University, 1984 M.Sc. Beijing Medical University, 1989 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER'S OF SCIENCE in THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF PHARMACOLOGY & THERAPEUTICS, FACULTY OF MEDICINE We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA AUGUST 1991 ©XUEPING, WANG, 1991 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. (Signature) Department of Pharmacology and Therapeutics Vancouver, Canada Date July 4th, 1992 DE-6 (2/88) ii ABSTRACT The objective of these experiments was to investigate the actions of a number of novel putative class III antiarrhythmic agents on the large conductance calcium-activated potassium channel (BKca) in cultured hippocampal neurons. The experiments were carried out in three steps. In the first set of experiments BKca channel, isolated from cultured rat hippocampal CA1 neuronal somatic membrane, was first identified and its physiological and pharmacological properties were characterized at a single channel level. This BKca channel had an average single channel conductance of 80 pS with physiological transmembrane K+ (140 mM inside and 5 mM outside). It was very selective to K+over Na+, a ratio of 100 to 7 was determined from this experiment. Calcium, at the internal side of the membrane, was necessary to activate the BKcaa channel. With low internal calcium concentration, depolarization could promote the rate of channel openings. An e-fold increase in p0 was found with 1 n M internal calcium and 15 mV depolarization. With 200 nM internal calcium, p0 was virtually independent of voltage. 0.1 mM external TEA showed fast blockade of this channel. Internal TEA and 4-AP (internal or external) showed no effect on BKca. In the second set of experiments, the actions of putative class III drugs on BKca was studied. The drugs were RP-62719, UK-68798, tedisamil (KC-8857) and risotilide (WY-48986) at concentrations 0.1 ~ 10uM. All these agents, applied both to the inside or to the outside of the patch membrane, resulted in the opening of the BKca channel to exhibit rapid flicking from open to nonconducting levels. This effect was dose-dependent and for KC-8857 and UK-68798 was evident at concentrations of 0.1 uM. The blocking rate constants were determined from a simple open channel blockade scheme and were not dependent on voltages. Single channel conductance and ionic selectivity were not affected by the drugs. The potencies for channel block of the drugs acting either externally or internally iii were in the order UK-68798>tedisamil>RP-62719> risotilide with UK-68798 reducing the mean open time of BKca by one-half at a concentration near 0.4/iM. In the final set of experiments, the thermodynamics associated with RP- 62719 block BKca channel was studied in order to better understand the molecular mechanisms of channel block. The Q10 associated with the channel mean open time was found to be 2.2 with 5 /iM RP-62719 at the inner surface of the patch membrane. The blocking and unblocking rate constants were determined using the simple open channel block scheme. Thermodynamic analysis, using transition rate theory, showed that the blocking rate constant was associated with a large increase in entropy. The relatively high temperature dependence for channel blockade was not consistent with a rate-limiting process established by simple diffusion of the agent to a channel blocking site. Channel block may involve conformational changes in the channel protein as a consequence of hydrophobic interactions between drug and channel sites. iv TABLE OF CONTENTS CHAPTER PAGE n ABSTRACT ii IV LIST OF TABLES vii V LIST OF FIGURES viii VI LIST OF LEGENDS x VH ACKNOWLEDGEMENT xii 1 INTRODUCTION 1 1.1 BACKGROUNDS OF SINGLE KCa CHANNEL STUDIES 1 1.1.1 KCa Classifications 1 1.1.2 BKCa Channels 2 1.1.2.1 BKca Channel Distributions and Function 2 1.1.2.2 Ca2+ Sensitivity and Selectivity of Ca2 + -Binding Sites 3 1.1.2.3 BKCa Channel Voltage Dependence 5 1.1.2.4 BKca Channel Selectivity and Conductance 5 1.1.2.5 BKCa Channel Gating Kinetics 6 1.1.2.6 BKCa Channel Pharmacology 7 2+ 2+ 1.1.2.6.1 Na + , Ca and Ba Blockade of BKCa 7 1.1.2.6.2 TEA Blockade of BKCa 8 1.1.2.6.3 Toxin Blockade of BKCa 8 1.1.3 SKCa Channels 10 1.1.3.1 SKfja Channels Distributions and Function 10 1.1.3.2 SKca Conductance and Calcium Dependence 11 TABLE OF CONTENTS (CONT'S) CHAPTER PAGE 1.1.3.3 SKCa Channel Pharmacology 11 1.1.4 Ca2+-activated K+ Currents in Hippocampal Neurons 12 1.2 SEQUENTIAL OPEN CHANNEL BLOCKADE MODEL 12 1.3 PATCH CLAMP TECHNIQUE 13 1.4 SYNTHETIC CLASS III ANTIARRHYTHMIC DRUGS 14 1.5 THERMODYNAMIC ANALYSIS 15 2 METHODS 19 2.1 CELL CULTURE PREPARATION 19 2.2 ELECTROPHYSIOLOGY 20 2.2.1 Glass and Pipettes 20 2.2.2 Mechanical Setup 21 2.2.3 Single Channel Patch-Clamp Configurations 21 2.2.4 Solutions Used 22 2.2.5 Recordings 25 2.2.6 Analysis Procedures 25 2.3 TEMPERATURE STUDIES 30 2.3.1 Equations for Thermodynamic Studies 31 3 RESULTS 33 3.1 IDENTIFICATION AND PROPERTIES OF SINGLE Krja CHANNELS 33 IN CULTURED RATCAl HIPPOCAMPAL NEURONS 3.1.1 Identification: Selectivity and Channel Conductance 33 3.1.2 Calcium Dependence 38 3.1.3 Voltage Dependence 39 vi TABLE OF CONTENTS (CONT'S) CHAPTER PAGE 3.1.4 Channel Kinetics 46 3.1.5 Pharmacology of BKCa Channel 49 3.2 ACTIONS OF ANTIARRHYTHMIC AGENTS ON BKCa 52 CHANNELS: SINGLE CHANNEL ANALYSIS 3.2.1 Inside-out Experiments 55 3.2.2 Outside-out Patch Experiments 63 3.3 THERMODYNAMIC STUDIES 69 3.3.1 Temperature Dependence of KCa Channel 72 3.3.2 Temperature Dependence of Drug Actions 79 4 DISCUSSION 91 4.1 BKCa CHANNEL PROPERTIES 91 4.2 OPEN CHANNEL BLOCKADE AS THE MECHANISM OF 92 CLASS III ANTIARRHYTHMICS BLOCK BKCa CHANNELS 4.3 MOLECULAR MECHANISM OF RP-62719 BLOCKADE 95 OF BKCa CHANNELS 5 REFERENCES 101 vii LIST OF TABLES TABLE PAGE Chemical Components of Solutions Used for Cell- 23 Attached and Excised Patch-Clamp Single Channel Studies Normalized Mean Open Time, Onward (Blocking) 68 Rate Constants for Drugs Transition State and Associated State 90 Thermodynamic Parameters viii LIST OF FIGURES FIGURE PAGE 1 Chemical Structures of Drugs Used for Experiments 24 2 Typical Records of Unitary Currents Passing 34 Through BKca in the Somatic Membrane of the Cultured Rat Hippocampal Neurons. 3 Current-Voltage Plots: KCa Channel Conductance 36 and Ion Selectivity 4 Calcium Dependency of BKCa Channel Behaviour 40 5 Calcium Dependency of BKCa Channel Kinetics 42-44 6 Voltage Dependence of BKCa 47 7 Kinetic Analysis of m 50 8 Effect of TEA on BKCa 53 9 Effect of RP-62719 on BKCa 56 10 Effect of RP-62719 on BKCa Channel Kinetics and 58 Current Amplitude 11 TO'-Drug Concentration Relationships 61 12 Voltage Dependence of RP-62719 Effect on BKCa 64 13 Effect of UK-68798, Tedisamil and Risotilide on 66 BKCa Channels 14 Effect of Drugs on BKCa at V = 0 mV; Outside-Out 70 Experiments 15 Temperature Dependence of BKCa Single-Channel 73 Currents 16 Temperature Dependence of BKCa Channel Mean 75 Open Time ix LIST OF FIGURES (Cont's) FIGURE PAGE 17 Effect of Temperature on BKrja Channel Kinetics 77 and Single-Channel Current Amplitudes 18 Temperature Dependence of RP-62719 Effects on 80 BKca Channel Behaviour 19 Temperature Dependence of RP-62719 Effects on 82 BKrja Channel Kinetics 20 Temperature Dependence of RP-62719 Effects on 84 BKfja Channel Mean Open Time (T0) 21 Arrhenius Plot for k2 87 X LIST OF LEGENDS FIGURE PAGE 2 Typical Records of Unitary Currents Passing 35 Through Kfja in the Somatic Membrane of the Cultured Rat Hippocampal Neurons 3 Current-Voltage Plots: KQ3 Channel Conductance 37 and Ion Selectivity 4 Calcium Dependency of BKCa Channel Behaviour 41 5 Calcium Dependency of BKfja Channel Kinetics 45 6 Voltage Dependence of BKca 48 7 Kinetic Analysis of BKCa 51 8 Effect of TEA on BKCa 54 9 Effect of RP-62719 on BKCa 57 10 Effect of RP-62719 on BKCa Channel Kinetics and 59 Single-Channel Current Amplitude 11 To'- Drug Concentration Relationships 62 12 Voltage Dependence of RP-62719 Effect on BKCa 65 13 Effect of UK-68798, Tedisamil and Risotilide on 67 BKfja Channel Behaviour 14 Effect of Drugs on BKCa at V = 0 mV; outside-out 71 Experiments 15 Temperature Dependence of BKfja Single-Channel 74 Currents in Control Solution 16 Temperature Dependence of BKCa Channel Mean 76 Open Time (To) 17 Effect of Temperature on BKca Channel Kinetics 78 and Single-channel Current Amplitude 18 Temperature Dependence of RP-62719 Effect on 81 BKfja Channel Behaviour xi LIST OF LEGENDS (Cont's) FIGURE PAGE 19 Temperature Dependence of RP-62719 Effect on 83 BKCa Channel Kinetics 20 Temperature Dependence of RP-62719 Effect on 85 BKCa Channel Mean Open Time (T0) 21 Arrhenius Plot for k2 88 xii ACKNOWLEDGMENTS: I would like to express my sincere appreciation to Dr.
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