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Structural Basis for Functional Modulation of Pentameric Ligand-Gated Ion Channels

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Structural Basis for Functional Modulation of Pentameric Ligand-Gated Ion Channels STRUCTURAL BASIS FOR FUNCTIONAL MODULATION OF PENTAMERIC LIGAND-GATED ION CHANNELS by YVONNE W. GICHERU Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Thesis Advisor: Sudha Chakrapani, Ph.D. Department of Physiology and Biophysics CASE WESTERN RESERVE UNIVERSITY May 2019 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of YVONNE W. GICHERU Candidate for the degree of Physiology and Biophysics* Witold Surewicz (Committee Chair) Matthias Buck Stephen Jones Vera Moiseenkova-Bell Rajesh Ramachandran Sudha Chakrapani March 27, 2019 *We also certify that written approval has been obtained for any proprietary material contained therein. Dedication To my family, friends, mentors, and all who have supported me through this process, thank you. Table of Contents List of Figures .................................................................................................... iv List of Abbreviations .......................................................................................... v Abstract .............................................................................................................. vi Chapter 1 ............................................................................................................. 1 Introduction .................................................................................................... 1 1.1 Pentameric ligand-gated ion channel (pLGIC) superfamily ...................... 2 1.2 pLGIC architecture ................................................................................... 4 1.3 Gating in pLGIC ....................................................................................... 7 1.4. Nicotinic acetylcholine receptors (nAChRs) .......................................... 10 1.5 Serotonin receptors (5-HT3R) ................................................................ 16 1.6 γ- Aminobutyric acid type A receptors (GABAAR) .................................. 24 1.7 Glycine receptors (GlyR) ........................................................................ 29 1.8 Prokaryotic receptors ............................................................................. 33 1.9 Purpose of this study ............................................................................. 37 Chapter 2 ........................................................................................................... 43 Allosteric modulation of pLGIC function by long chain polyunsaturated fatty acids (PUFAs) ...................................................................................... 43 Introduction .................................................................................................. 44 Results ......................................................................................................... 50 DHA modulates the pH-elicited response in GLIC ....................................... 50 Structural changes associated with DHA binding in GLIC ........................... 53 AA and EPA modulate the pH-elicited response in GLIC ............................. 55 i PUFA effect on 5-HT3AR function ................................................................. 56 Membrane environment for structural studies .............................................. 57 Discussion ................................................................................................... 58 Methods ....................................................................................................... 61 Chapter 3 ........................................................................................................... 78 Understanding allosteric and orthosteric inhibition mechanisms of the 5- HT3A receptor ............................................................................................... 78 Introduction .................................................................................................. 79 Results ......................................................................................................... 85 Cannabinoid inhibition of 5-HT3AR currents ................................................. 85 Ligand binding sites in 5-HT3AR ................................................................... 85 Granisetron inhibition of 5-HT3AR currents ................................................... 87 Granisetron binding and conformational changes ........................................ 88 Discussion ................................................................................................... 92 Methods ....................................................................................................... 95 Chapter 4 ......................................................................................................... 114 A commentary on the relevance of a membrane environment for ion channel gating ........................................................................................... 114 Foreword ................................................................................................... 115 Introduction ............................................................................................... 116 Impact of membrane environment on channel gating and dynamics .... 117 New insights from noncanonical domain changes? ............................... 120 Chapter 5 ......................................................................................................... 123 Discussion and future directions ................................................................ 123 Discussion ................................................................................................. 124 ii Future directions ........................................................................................ 128 Appendix ......................................................................................................... 133 References ...................................................................................................... 134 iii List of Figures Figure 1. 1: A schematic representation of the topology and arrangement in pLGICs. ... 39 Figure 1. 2: nAChR structure from Torpedo membranes. ............................................... 40 Figure 1. 3: Representative eukaryotic pLGIC structures. .............................................. 41 Figure 1. 4: Representative prokaryotic pLGICs. ............................................................ 42 Figure 2. 1: Essential long chain polyunsaturated fatty acids (PUFAs). .......................... 66 Figure 2. 2: DHA modulation of GLIC function ................................................................ 67 Figure 2. 3: Effect of DHA on GLIC desensitization. ....................................................... 68 Figure 2. 4: Effect of DHA pre-application on GLIC currents. ......................................... 69 Figure 2. 5: DHA has no effect on the non-desensitizing GLIC I9A/H11F mutant. ........ 70 Figure 2. 6: Lack of DHA effect on the non-desensitizing GLIC I9A/H11F mutant. ....... 71 Figure 2. 7: DHA binding site in GLIC. ............................................................................ 72 Figure 2. 8: R118A mutation reduces the effect of DHA on desensitization. .................. 73 Figure 2. 9: Conformational changes in the GLIC pore. .................................................. 74 Figure 2. 10: EPA and AA modulation of GLIC function.................................................. 75 Figure 2. 11: DHA, EPA and AA effect on 5-HT3AR function. .......................................... 76 Figure 2. 12: Changes in M4 distance measured by DEER for GLIC in nanodiscs. ....... 77 Figure 3. 1: Endocannabinoids and phytocannabinoids. .............................................. 101 Figure 3. 2: Cannabinoid modulation of 5-HT3AR function. ........................................... 102 Figure 3. 3: Cryo-EM reconstruction of THC-5HT-bound full-length 5-HT3AR. .............. 103 Figure 3. 4: Comparison of serotonin-bound 5-HT3AR with 5-HT3AR-THC-5HT. ........... 104 Figure 3. 5: Granisetron inhibition of 5-HT3AR currents. ................................................ 105 Figure 3. 6: Cryo-EM structure of granisetron-bound full-length 5-HT3AR. .................... 106 Figure 3. 7: The granisetron-binding site. ..................................................................... 107 Figure 3. 8: Differences between granisetron and tropisetron binding poses. .............. 108 Figure 3. 9: Conformational differences between the apo and ligand-bound states. .... 109 Figure 3. 10: Effects of mutations at the ligand-binding pocket..................................... 111 Figure 3. 11: Functional characterization of R65A 5-HT3AR. ......................................... 113 iv List of Abbreviations α-Bgx α-Bungarotoxin AA cis-5,8,11,14-Eicosatetraenoic acid AChBP Acetylcholine binding protein 2-AG 2-arachidonoylglycerol AEA N-arachidonoylethanolamine CBD Cannabidiol CNS Central nervous system Cryo-EM Cryo-electron microscopy DHA cis-4,7,10,13,16,19-Docosahexaenoic acid EC Endocannabinoid ECS Endocannabinoid system EPA cis-5,8,11,14,17-Eicosapentaenoic acid ELIC Erwinia chrysanthemi ligand-gated ion channel GI Gastrointestinal GLIC Gloeobacter violaceous ligand-gated ion channel GABAAR γ-aminobutyric acid receptor type A GlyR Glycine receptor 5-HT3AR Serotonin receptor type 3A 5-HT Serotonin MDs Molecular dynamics simulations nAChR Nicotinic acetylcholine receptor PLGIC Pentameric ligand-gated
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