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Interactions of Insecticidal Spider Peptide Neurotoxins with Insect Voltage- and Neurotransmitter-Gated Ion Channels

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Interactions of Insecticidal Spider Peptide Neurotoxins with Insect Voltage- and Neurotransmitter-Gated Ion Channels Interactions of insecticidal spider peptide neurotoxins with insect voltage- and neurotransmitter-gated ion channels (Molecular representation of - HXTX-Hv1c including key binding residues, adapted from Gunning et al, 2008) PhD Thesis Monique J. Windley UTS 2012 CERTIFICATE OF AUTHORSHIP/ORIGINALITY I certify that the work in this thesis has not previously been submitted for a degree nor has it been submitted as part of requirements for a degree except as fully acknowledged within the text. I also certify that the thesis has been written by me. Any help that I have received in my research work and the preparation of the thesis itself has been acknowledged. In addition, I certify that all information sources and literature used are indicated in the thesis. Monique J. Windley 2012 ii ACKNOWLEDGEMENTS There are many people who I would like to thank for contributions made towards the completion of this thesis. Firstly, I would like to thank my supervisor Prof. Graham Nicholson for his guidance and persistence throughout this project. I would like to acknowledge his invaluable advice, encouragement and his neverending determination to find a solution to any problem. He has been a valuable mentor and has contributed immensely to the success of this project. Next I would like to thank everyone at UTS who assisted in the advancement of this research. Firstly, I would like to acknowledge Phil Laurance for his assistance in the repair and modification of laboratory equipment. To all the laboratory and technical staff, particulary Harry Simpson and Stan Yiu for the restoration and sourcing of equipment - thankyou. I would like to thank Dr Mike Johnson for his continual assistance, advice and cheerful disposition. I would like to express gratitude to Dr Stella Valenzuela for her tutoring in cell culture and molecular biology techniques. Additionally, I would like to thank all my friends at UTS who have made this journey with me. To all those from the NRG laboratory who have accompanied me throughout my research I would like to express my greatest thanks. I would like to thank Fran Marcon, Dr Julia Ting and Dr Ben Blacklow for their support and friendship. I also would like to thank Michelle Little for her friendship and her invaluable tutoring and assistance in the laboratory. To Dr Simon Gunning and Youmie Chong, I would like to express my gratitude for their tutoring in electrophysiological techiques. In addition, I would also like to acknowledge Dr Pierre Escoubas for his collaboration and friendship over the years of this project. Finally, to whom I owe a great deal of thanks, I would like to acknowledge my friends and family. I would like to thank everyone who has supported and encouraged me throughout my PhD. In particular I express my deepest gratitude to my parents for their continual patience, encouragement and faith in my abilities. Their support has been invaluable and I cannot express enough gratitude. Lastly, but most importanty, to my husband Josh who has been constantly by my side, I would like to express my greatest thanks. He has always been willing to listen, support and encourage me throughout these past years and I could not have achieved what I have without him. To everyone who has supported, encouraged and kept me in their prayers, I express my profound thanks. Through God all things are possible, Matt; 19:26. iii Table of Contents Table of figures ....................................................................................................................... vi Tables ..................................................................................................................................... vii Abstract ................................................................................................................................... ix Abbreviations .......................................................................................................................... xi Publications arising from this thesis .......................................................................................xv Chapter One ......................................................................................................................... - 1 - 1. 1 The global insect pest problem ................................................................................. - 2 - 1.1.1 Agricultural pests ................................................................................................ - 2 - 1.1.2 Vectors of disease ............................................................................................... - 2 - 1.2 Health consequences and environmental impacts ..................................................... - 4 - 1.2.1 Insecticide resistance .......................................................................................... - 5 - 1.3 Bioinsecticides as natural insect pest control agents ................................................. - 6 - 1.4 Spider venoms: sources of novel bioinsecticides ...................................................... - 6 - 1.5 Spider venom peptide nomenclature ......................................................................... - 8 - 1.6 Structure of the precursor spider venom peptide and post-translational processing . - 8 - 1.7 Structural motifs of spider venom peptides: variations on an ancestral fold ............. - 9 - 1.8 Insecticidal targets of spider neurotoxins ................................................................ - 13 - 1.8.1 Spider venom peptides targeting insect NaV channels ...................................... - 13 - 1.8.2 Spider venom Peptides Targeting Insect CaV Channels ................................... - 19 - 1.8.3 Spider venom peptides targeting insect KV channels ....................................... - 23 - 1.8.4 Linear spider peptide toxins targeting the cell membrane ................................ - 25 - 1.8.5 Spider venom toxins targeting presynaptic nerve terminals ............................. - 25 - 1.8.6 Spider venom toxins targeting glutamate receptors .......................................... - 26 - 1.9 Insecticides targeting neurotransmitter receptors .................................................... - 27 - 1.9.1 Insecticides targeting nACh receptors .............................................................. - 27 - 1.9.2 Insecticides targeting GABA receptors ............................................................ - 29 - 1.10 Bioinsecticide lead selection .................................................................................. - 30 - 1.11 Manufacturing spider venom toxins as insecticides .............................................. - 33 - 1.12 Project aims and concluding remarks .................................................................... - 37 - Chapter Two ...................................................................................................................... - 39 - 2.1 Selection and isolation of insect neurons: dorsal unpaired median (DUM) neurons- 40 - 2.1.1 Supply and maintenance of cockroaches .......................................................... - 44 - 2.1.2 Acute Isolation of DUM Neurons ..................................................................... - 44 - 2.1.3 Coverslip preparation ........................................................................................ - 45 - 2.2 Toxin source and storage ......................................................................................... - 46 - iv 2.2.1 Hadronyche versuta venom .............................................................................. - 46 - 2.3 Insect lethality assays .............................................................................................. - 47 - 2.3.1 Supply of crickets ............................................................................................. - 47 - 2.3.2 Acute toxicity testing ........................................................................................ - 47 - 2.4 Whole-cell patch-clamp protocols ........................................................................... - 48 - 2.4.1 Voltage-activated currents ................................................................................ - 48 - 2.4.2 Transmitter-activated currents .......................................................................... - 56 - 2.4.3 Current-clamp: action potential protocols ........................................................ - 60 - 2.4.4 Experimental procedures .................................................................................. - 61 - 2.5 Curve-fitting and statistical analysis ........................................................................ - 65 - 2.6 Sources of chemicals ............................................................................................... - 66 - Chapter Three: Windley et al., 2011 .................................................................................. - 67 - Chapter Four ...................................................................................................................... - 81 - 4.1 Introduction .............................................................................................................. - 82 - 4.2 Results ...................................................................................................................... - 85 - 4.2.1 Diselenide -HXTX-Hv1c ................................................................................ - 85 - 4.2.2 Effects of native and diselenide -HXTX-Hv1c on BKCa channels ................
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