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Ethanol-Oxytocin Interactions at Homomeric Glycine Receptors

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Ethanol-Oxytocin Interactions at Homomeric Glycine Receptors Ethanol-oxytocin Interactions at Homomeric Glycine Receptors A thesis submitted to fulfil requirements for the degree of Master of Philosophy - Dominique Taylor Faculty of Pharmacy The University of Sydney 2018 Statement of Authorship & Originality This is to certify that to the best of my knowledge, the content of this thesis is my own work. This thesis has not been submitted for any degree or other purposes. I certify that the intellectual content of this thesis is the product of my own work and that all the assistance received in preparing this thesis and sources have been acknowledged. Dominique Taylor Acknowledgements I would like to acknowledge my supervisor Dr Mary Collins (Chebib) for her expert advice throughout my project. Thanks to my co-supervisors Dr Nathan Absalom for all of his assistance in practical and theoretical aspects of the research; and Dr Michael Bowen for all his assistance. I would also like to thank Dr Steven Devenish for his expertise on glycine receptors, and for generous assistance in supply and manufacture of glycine receptors. I’m also grateful to all the other members of the lab; (including but not limited to) Tim Bakas, Dr Petra van Nieuwenhuijzen, Dr Vivian Liao, Dinesh Indurthi, Taima Quddah, Dr Philip Ahring, Leonny Hartiadi, for their company and frequent guidance in standard lab activities. A special mention to my husband Ben, along with Henry, Charlie, Tilly, Lulu, Jack and Scruff Johansson, who differentially supported, distracted, confused, and amused me throughout this endeavour. Justin and Stacey Taylor also get a shout out for bestowing me with some of their mad critical thinking skills. [ii] Contents Statement of Authorship & Originality .......................................................................................... ii Acknowledgements ........................................................................................................................ ii List of Figures ................................................................................................................................. v List of Tables .................................................................................................................................. v List of Abbreviations ..................................................................................................................... vi Abstract ........................................................................................................................................ vii Chapter 1: All About Alcohol’s Actions .......................................................................................... 1 1.1 GABAA Receptors Mediate Many of Alcohol’s Effects ........................................................ 3 1.1.1 GABAA Receptor Functions and Properties .................................................................. 4 1.1.2 Characteristics of δ Subunit-Containing Receptors ..................................................... 4 1.1.3 Why are δ-GABAA Receptors a Likely Target? ............................................................. 6 1.2 A Review of Glycine Receptors ........................................................................................... 7 1.2.1 Glycine Receptor Subunits Influence Receptor Characteristics ................................. 10 1.3 Glycine Receptors Mediate Ethanol Effects and Behaviours ............................................ 12 1.3.1 Ethanol Modulates Glycine Receptors in Reward Pathways ..................................... 13 1.3.2 Zinc and Ethanol Synergistically Modulate Glycine Receptors .................................. 14 1.3.3 Mechanism of Ethanol Action at Glycine Receptors .................................................. 15 1.4 Oxytocin-ethanol Interactions at Glycine Receptors ........................................................ 16 1.4.1 Oxytocin and Alcohol ................................................................................................. 18 1.4.2 Oxytocin-ethanol Interactions at Ligand-gated Ion Channels ................................... 19 1.5 Research Question & Aims ................................................................................................ 21 1.5.1 Significance ................................................................................................................ 21 Chapter 2: Experimental Procedures .......................................................................................... 22 2.1 Molecular Biology ............................................................................................................. 22 2.1.1 Materials .................................................................................................................... 22 2.1.2 Transformation & Growth of DNA Plasmids .............................................................. 22 2.1.3 Linearisation and Transcription of DNA ..................................................................... 23 2.1.4 Site-Directed Mutagenesis ......................................................................................... 23 2.2 Electrophysiology .............................................................................................................. 24 2.2.1 Materials .................................................................................................................... 24 2.2.2 Xenopus laevis Oocyte Preparation ........................................................................... 24 2.2.3 Expression of Recombinant Glycine Receptors in Xenopus Oocytes ......................... 25 2.2.4 Electrophysiological Recording from Recombinant Receptors .................................. 26 2.2.5 Data and Statistical Analysis ...................................................................................... 27 Chapter 3: Results ....................................................................................................................... 28 [iii] 3.1 Expression of Homomeric Glycine Receptors in Xenopus Oocytes .................................. 28 3.2 Effects of Ethanol on Wild Type α1 and α2 Glycine Receptors ........................................ 31 3.2.1 Zinc-induced Potentiation of α1 Glycine Receptors .................................................. 33 3.3 Oxytocin-glycine Interactions at α1 and α2 GlyRs ............................................................ 34 3.4 Ethanol-oxytocin Interactions at Wild Type α1 GlyRs....................................................... 35 3.5 Ethanol-oxytocin Interactions at α2 GlyRs ........................................................................ 37 3.6 Ethanol-oxytocin Interactions at α1δL2 Glycine Receptors .............................................. 39 Chapter 4: Discussion and Conclusion ......................................................................................... 41 4.1 Ethanol-induced Potentiation of Glycine Receptors ......................................................... 41 4.1.1 Zinc Modulation of α1 GlyRs ...................................................................................... 43 4.2 Interactions of Oxytocin and Ethanol ............................................................................... 43 4.2.1 Vasopressin Does Not Modulate Ethanol’s Effects .................................................... 45 4.2.2 Oxytocin May Interact with Zinc at α1 GlyRs ............................................................. 46 4.3 Oxytocin-ethanol Interactions at α1δL2 GlyRs ................................................................. 47 4.4 Conclusion and Further Considerations ............................................................................ 48 4.4.1 Further Considerations and Future Directions .......................................................... 49 4.4.2 Limitations of These Experiments .............................................................................. 50 References .................................................................................................................................. 52 [iv] List of Figures Figure 1. Ethanol binding sites at αβδ/γ GABAA receptors ........................................................... 6 Figure 2. Schematic diagram of the ECD and subunit composition of glycine receptors ............. 7 Figure 3. Structural and binding properties of an α1 homomeric GlyR ........................................ 9 Figure 4. Ethanol binding pocket at the α1 subunit of the glycine receptor. ............................. 16 Figure 5. The Molecular Structure of Nonapeptides Oxytocin and Arginine Vasopressin ......... 18 Figure 6. Microinjection of mRNA into Xenopus laevis oocyte. ................................................. 25 Figure 7. Two-electrode voltage clamp schematic diagram ....................................................... 26 Figure 8. C-R curves for glycine at α1 and α2 WT GlyRs ............................................................. 28 Figure 9. C-R curve comparison of α1dL2 mutant and α1 GlyRs ................................................ 30 Figure 10. Ethanol induced potentiation of wild type α1 and α2 receptors .............................. 32 Figure 11. Zinc modulates activity at α1 GlyRs ........................................................................... 33 Figure 12. Effects of oxytocin on glycine-gated current at WT GlyRs ......................................... 34 Figure 13. Summary of oxytocin-ethanol interactions at α1 GlyRs ...........................................
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