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Uncovering the Molecular Mechanisms for Propofol and Volatile Anesthetics University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Shedding Light On General Anesthesia: Uncovering The Molecular Mechanisms For Propofol And Volatile Anesthetics Kellie Ann Woll University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Molecular Biology Commons, Neuroscience and Neurobiology Commons, and the Pharmacology Commons Recommended Citation Woll, Kellie Ann, "Shedding Light On General Anesthesia: Uncovering The Molecular Mechanisms For Propofol And Volatile Anesthetics" (2017). Publicly Accessible Penn Dissertations. 2641. https://repository.upenn.edu/edissertations/2641 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2641 For more information, please contact [email protected]. Shedding Light On General Anesthesia: Uncovering The Molecular Mechanisms For Propofol And Volatile Anesthetics Abstract General anesthetics have played a pivotal role in the history of medicine. Despite accounts of their use within the earliest of human records, our understanding of anesthetic mechanisms remains unclear. Understanding these molecular mechanisms would be a significant advance toward enhanced drug design and optimal the clinical use of these potentially hazardous agents. Recent advances in chemical and molecular biology, including photoaffinity labeling, vha e allowed enhanced appreciation of the complex interactions anesthetic’s have with their macromolecular substrates. This work is dedicated to further define the protein interactions of the frequently administered volatile anesthetics sevoflurane and isoflurane, as well as the most commonly used intravenous anesthetic, propofol. A novel photoaffinity ligand for sevoflurane was validated and applied to uncover the unique mechanism of sevoflurane positive modulation of mammalian Shaker Kv1.2 channels. This novel sevoflurane photoaffinity ligand was in addition to a previously developed photoaffinity ligand for isoflurane, further applied to determine the anesthetic binding sites within a vital protein target, synaptic GABAA receptors. The molecular recognition elements for propofol-protein interactions were probed using a novel hydrogen-bond null derivative. It was determined that the propofol 1-hydroxyl is key for molecular interactions that contribute to anesthetic endpoints, such as synaptic GABAA receptor positive modulation, while less significant for other known biological effects like decreasing muscle contractility. The range of propofol-binding proteins within synaptosomes was further defined with the synthesis of a novel photoaffinity tandem click chemistry-active ligand and the development of a quantitative affinity-based protein profiling workflow. Results of the investigation indicated a highly complex pool of propofol-specific proteins including an unbiased, selective binding of specific synaptic GABAA eceptr or subunits. The likely propofol binding cavities and the underlining molecular recognition features that contribute to the selective GABAA receptor subunit binding were examined using molecular dynamics simulations and photoaffinity protection studies. Together these series of studies suggest that general anesthetics bind a to range of molecular substrates that cumulatively result in general anesthesia phenotypes and that multiple, functionally distinct, binding sites can be present within a single protein target. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Pharmacology First Advisor Max B. Kelz Keywords Chemical Biology, General Anesthetics, Isoflurane, Photoaffinity Labeling, Propofol Subject Categories Molecular Biology | Neuroscience and Neurobiology | Pharmacology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2641 SHEDDING LIGHT ON GENERAL ANESTHESIA: UNCOVERING THE MOLECULAR MECHANISMS OF PROPOFOL AND VOLATILE ANESTHESTICS Kellie Ann Woll A DISSERTATION in Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2017 Supervisor of Dissertation: ________________________ Roderic G. Eckenhoff, MD, Austin Lamont Professor of Anesthesiology & Critical Care Graduate Group Chairperson: _________________________ Julie A. Blendy, PhD, Professor of Pharmacology Dissertation Committee: Max B. Kelz, MD PhD, David E. Longnecker Associate Professor of Anesthesiology and Critical Care Ivan J. Dmochowski, PhD, Professor of Chemistry Benjamin A. Garcia, PhD, Presidential Professor of Biochemistry and Biophysics Vladimir R. Muzykantov, MD PhD, Professor of Pharmacology SHEDDING LIGHT ON GENERAL ANESTHESIA: UNCOVERING THE MOLECULAR MECHANISMS OF PROPOFOL AND VOLATILE ANESTHESTICS COPYRIGHT 2017 Kellie Ann Woll ACKNOWLEDGEMENTS I have been fortunate enough to have encountered and continue to be surrounded by the most amazing people, and they are largely responsible for allowing me to reach this stage in my life and career. At the forefront I must thank Rod and Maryellen Eckenhoff for their support and guidance. Under their mentorship I have not only developed as a scientist, but also as a person. I will forever be grateful for the astounding opportunities that they have provided me and will continue look up to them for the rest of my life. The UPenn Anesthesiology Department as a whole has been a strong force in pushing me forward. In all honestly the ‘JMB3 Attic’ ended up as home-away-from- home for the past four years, and the individuals that work here became like family. Thank you all for your mentorship and friendship; I will always be in-debt to you. I would also like to thank the previous mentors and peers that significantly changed the course of my life, and ultimately lead me into science research. These include my undergraduate mentor Debbie Crans as well as my steadfast friend Robin Ward. I can’t tell you how much you have impacted my life and I thank you so much for helping me find my passion. Finally, and most importantly, I would like to thank those who have supported me throughout my life. I have put my family through quite a bit; despite this they have always stood behind me and encouraged me to reach for my dreams. I struggle to put into words how much your support and love has helped me find my way in the most trying times of my life. I hope to make you at least half as proud as I am of all of you. Thank you. -‘Persist & persevere’- iii ABSTRACT SHEDDING LIGHT ON GENERAL ANESTHESIA: UNCOVERING THE MOLECULAR MECHANISMS OF PROPOFOL AND VOLATILE ANESTHESTICS Kellie A. Woll Roderic G. Eckenhoff General anesthetics have played a pivotal role in the history of medicine. Despite accounts of their use within the earliest of human records, our understanding of anesthetic mechanisms remains unclear. Understanding these molecular mechanisms would be a significant advance toward enhanced drug design and optimal the clinical use of these potentially hazardous agents. Recent advances in chemical and molecular biology, including photoaffinity labeling, have allowed enhanced appreciation of the complex interactions anesthetic’s have with their macromolecular substrates. This work is dedicated to further define the protein interactions of the frequently administered volatile anesthetics sevoflurane and isoflurane, as well as the most commonly used intravenous anesthetic, propofol. A novel photoaffinity ligand for sevoflurane was validated and applied to uncover the unique mechanism of sevoflurane positive modulation of mammalian Shaker Kv1.2 channels. This novel sevoflurane photoaffinity ligand was in addition to a previously developed photoaffinity ligand for isoflurane, further applied to determine the anesthetic binding sites within a vital protein target, synaptic GABAA receptors. The molecular recognition elements for propofol-protein interactions were probed using a novel hydrogen-bond null derivative. It was determined that the propofol 1-hydroxyl is key for molecular interactions that contribute to anesthetic endpoints, such as synaptic GABAA receptor positive modulation, while less significant for other known iv biological effects like decreasing muscle contractility. The range of propofol-binding proteins within synaptosomes was further defined with the synthesis of a novel photoaffinity tandem click chemistry-active ligand and the development of a quantitative affinity-based protein profiling workflow. Results of the investigation indicated a highly complex pool of propofol-specific proteins including an unbiased, selective binding of specific synaptic GABAA receptor subunits. The likely propofol binding cavities and the underlining molecular recognition features that contribute to the selective GABAA receptor subunit binding were examined using molecular dynamics simulations and photoaffinity protection studies. Together these series of studies suggest that general anesthetics bind a to range of molecular substrates that cumulatively result in general anesthesia phenotypes and that multiple, functionally distinct, binding sites can be present within a single protein target. v TABLE OF CONTENTS ACKNOWLEDGEMENTS…………………………………………………….........…iii ABSTRACT…………………………………………………………………….…….….iv LIST OF TABLES……………………………………………………………………….x LIST OF ILLISTRATIONS..…………………………………………………………..xi CHAPTER 1: INTRODUCTION TO GENERAL ANESTHESA & PHOTOAFFINITY LABELING………………………………………………………..1 1.1 Brief Historical Sketch………………………………………………………………..2
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