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Palmitoylation of Caveolin-1 and Its Importance for Structural and Functional Plasticity

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Palmitoylation of Caveolin-1 and Its Importance for Structural and Functional Plasticity Palmitoylation of Caveolin-1 and its importance for structural and functional plasticity A DISSERTATION SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY Katherine R. Tonn IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Paul G. Mermelstein November 2018 © Katherine R. Tonn Eisinger 2018 Acknowledgments I would like to thank my adviser, Dr. Paul Mermelstein, for his mentorship, training, support, and scientific flexibility. Infinite thanks to past and present members of the Mermelstein and Meisel Labs, especially Dr. Brittni Peterson, Dr. Kelsey Moore, Dr. Laura Been, Dr. Luis Martinez, Dr. Valerie Hedges, and Dr. John Meitzen, for being a source of scientific inspiration and friendship. I could not have asked for a better friend and lab colleague than Dr. Kellie Gross, whose input has kept me sane and made me a better scientist. Thanks also to stellar undergrads Kerry Trotter, Julia Dworsky, and Sam Swanson for their help and energy. Thanks to the many people who collaborated or helped in some way on the experiments presented in this thesis, including Dr. Mark Thomas, Dr. Lorene Lanier, Dr. Mark Dell’Acqua, Dr. Kevin Woolfrey, Dr. Brian Head, Dr. Jing Tong, and Dr. John Meitzen. In particular, I am extremely grateful for the collaboration of Dr. Lorene Lanier, whose enthusiasm helped reinvigorate me and this project. Finally, thanks to the members of my thesis committee, Drs. Harry Orr, Timothy Ebner, Anna Lee, and Robert Meisel, for their encouragement and guidance. i Dedication For Mom, my first and most important example of what it is to be smart, versatile, and kind. For Dad, who fostered my sense of curiosity, and taught me to be comfortable with the contents of a toolbox. For Gina, whose intelligence, passion, ambition, and star power give me something to strive for. For Bob, who gets it. And me. ii Abstract This dissertation examines the regulation and function of caveolin-1 (Cav1). Cav1 is an integral membrane protein that creates functional microdomains of neuronal proteins within lipid rafts. Cav1 regulates a variety of signaling pathways, including mGluR-activated G protein cascades, and is involved in membrane trafficking of proteins such as estrogen and dopamine receptors. The function of Cav1 is regulated by palmitoylation, a reversible post-translational addition of a 16-carbon lipid chain that is involved in trafficking and compartmentalizing target proteins. This regulatory mechanism is important not only for Cav1, but also for membrane association of estrogen receptors. Within the nervous system, palmitoylation of estrogen receptor alpha (ERα) is necessary for surface membrane localization and mediation of downstream signaling through the activation of metabotropic glutamate receptors (mGluRs). Mutation of the single palmitoylation site on ERα prevents its physical association with Cav1, which in turn is required for the formation of the estrogen receptor/mGluR signaling complex. Interestingly, siRNA knockdown of either of two palmitoyl acyltransferases, DHHC7 or DHHC21, also eliminates this signaling mechanism. As ERα has only one palmitoylation site, I hypothesized that one of these DHHCs palmitoylates another essential protein in this signaling complex, namely Cav1. I investigated this using an acyl-biotin exchange assay in HEK293 cells in conjunction with DHHC overexpression, and found that DHHC7 increased Cav1 palmitoylation. Mutation of the palmitoylation sites on Cav1 eliminated this effect, but did not disrupt the ability of the DHHC enzyme to associate with the protein. In contrast, siRNA knockdown of DHHC7 alone was not sufficient to decrease Cav1 palmitoylation, but rather required simultaneous knockdown of DHHC21. iii These findings raise questions about the overall influence of palmitoylation on the membrane-initiated estrogen signaling pathway, and highlight the importance of considering the influence of palmitoylation on other Cav1-dependent processes. Additionally, recent studies have shown that altering Cav1 expression influences neuronal plasticity and related behaviors in contexts ranging from learning and memory to chronic injury. Given this relationship between Cav1 and experience-dependent plasticity, I hypothesized that Cav1 expression would also be involved in drug-induced changes in neuronal signaling. I utilized a locomotor sensitization paradigm to test this hypothesis. Animals receiving repeated cocaine displayed behavioral sensitization and greater expression of Cav1 mRNA in the nucleus accumbens when compared to saline- treated controls. Overexpression of Cav1 in the nucleus accumbens enhanced cocaine- induced locomotor responses to cocaine, while Cav1 KO animals did not sensitize. Cultured neurons from the nucleus accumbens, a brain region critical for the development of sensitization, had enhanced dendritic complexity in Cav1 KO mice and altered responses to cocaine. Finally, I report that Cav1 palmitoylation is required for its normal function. Together, these findings suggest that (1) Cav1 KO mice may be structurally saturated such that normal drug-induced plasticity is prevented, (2) Cav1 palmitoylation plays an important role in facilitating the proper activity of signaling molecules associated with Cav1, and (3) understanding Cav1 function will be necessary for fully understanding the development of addiction. iv Table of Contents Acknowledgments................................................................................................................ i Dedication ........................................................................................................................... ii Abstract .............................................................................................................................. iii List of Tables .................................................................................................................... vii List of Figures .................................................................................................................. viii CHAPTER 1: Introduction and Literature Review ............................................................. 1 Caveolin proteins ...................................................................................................... 2 Classical nuclear vs. membrane-associated estrogen receptors ................................ 3 Estrogen-Sensitive Membrane Receptors ............................................. 5 mGluRs: A link to intracellular signaling pathways ................................................. 6 ER-mGluR Interactions ........................................................................ 8 Membrane-associated ER-mGluR Interactions in Medium Spiny Neurons ............................................................................................... 12 Caveolin organizes functional signaling microdomains ......................................... 13 Palmitoylation: Regulating membrane interactions ................................................ 16 Purpose and Aims ................................................................................................... 22 CHAPTER 2: Palmitoylation of Caveolin-1 is regulated by the same DHHC enzymes as steroid hormone receptors ................................................................................................. 23 Introduction ............................................................................................................. 24 Methods .................................................................................................................. 25 Results ..................................................................................................................... 33 Discussion ............................................................................................................... 45 CHAPTER 3: Caveolin-1 and cocaine-induced plasticity ................................................ 51 Introduction ............................................................................................................. 52 Methods .................................................................................................................. 53 Results ..................................................................................................................... 59 Discussion ............................................................................................................... 70 CHAPTER 4: Overall discussion and conclusions ........................................................... 75 v Importance of Cav1 for ER/mGluR signaling ........................................................ 76 ER/mGluR relationship ....................................................................... 76 Sex differences .................................................................................... 78 Cav1 and drug-induced plasticity ........................................................................... 81 Cav1 interacts with and/or influences many signaling molecules associated with drug-induced plasticity .............................................. 82 The nucleus accumbens and medium spiny neurons .......................... 86 Conclusion .............................................................................................................. 88 References ......................................................................................................................... 89 vi List of Tables Table 1.1. ER – mGluR functional interactions
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