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Modulation of Ca2+ Signaling by Trimeric Intracellular Cation

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Modulation of Ca2+ Signaling by Trimeric Intracellular Cation Channels in the Heart Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Xinyu Zhou Ohio State University Biochemistry Program The Ohio State University 2019 Dissertation Committee Dr. Jianjie Ma, Advisor Dr. Jill Rafael-Fortney Dr. Hua Zhu Dr. Jian-Qiu Wu Copyrighted by Xinyu Zhou 2019 Abstract Trimeric intracellular cation channels, called TRIC-A and TRIC-B, are distributed to intracellular Ca2+ stores and mainly mediate the permeability of K+ ions in multiple cell types. Previously we showed that genetic ablation of TRIC-A leads to compromised K+- permeability and Ca2+ release in the muscle sarcoplasmic reticulum (SR), supporting the hypothesis that TRIC channels function as counter-ion channels during the acute phase of Ca2+ release under physiological conditions. In cardiomyocytes, spontaneous Ca2+ waves, triggered by store overload-induced Ca2+ release (SOICR) mediated by the type 2 ryanodine receptor (RyR2), develop extra-systolic contractions often associated with arrhythmic events. In this study, we found that the carboxyl-terminal tail domain of TRIC-A (CTT-A) interacts with the RyR2 channel to directly modulate SOICR activity. Biochemical studies demonstrate direct interaction between CTT-A and RyR2. In HEK293 cells with stable expression of RyR2, transient expression of TRIC-A, but not TRIC-B, leads to apparent suppression of spontaneous Ca2+ oscillations. Ca2+ measurements using the cytosolic indicator Fura-2 and the ER luminal store indicator D1ER suggest that TRIC-A enhances Ca2+ leak across the ER membrane by directly targeting to RyR2 to modulate SOICR. Moreover, synthetic CTT-A peptide facilitates RyR2 channel activity in the lipid bilayer ii reconstitution system and induces intracellular Ca2+ release after micro-injection into isolated cardiomyocytes, whereas such effects were not observed with the CTT-B peptide. Therefore, in addition to the ion-conducting function, TRIC-A seems to function as an accessory protein of RyR2 to modulate SR Ca2+ handling in cardiac muscle. Although Tric-a-/- mice do not display significant abnormity in the heart under resting condition, isoproterenol induced stress condition would induce abnormal cardiac function and fibrosis. Moreover, Tric-a-/- heart is more susceptible to Transverse Aortic Constriction (TAC) induced heart injury and develop cardiac fibrosis and hypertrophy. These results suggested that the stress resistance capacity is significantly compromised in Tric-a-/- heart. Using isolated cardiomyocytes, we indentified altered SR Ca2+ uptake as well as altered mitochondria Ca2+ uptake in the Tric-a-/- cardiomyocytes indicating that TRIC-A played a role in SR-mitochondria Ca2+ cross-talk. In summary, our results demonstrate the crucial role of TRIC-A in regulating both SR and mitochondria Ca2+ homeostasis. TRIC-A could directly interact with RyR2 and regulate its activity to maintain normal SR Ca2+ homeostasis. Cardiomyocytes lacking TRIC-A would not only cause impaired SR Ca2+ signaling, but also affect mitochondria Ca2+ homeostasis through SR-mitochondria cross-talk which leads to compromised mitochondria stability under stress condition and ultimately results in cardiac fibrosis and hypertrophy. iii Acknowledgments I would like to present my deepest gratitude to Professor Jianjie Ma, for his guidance and encouragement throughout my PhD period. I would like to thank him for all of his hard work in mentoring me and helping me with this thesis. I would also like to convey my thanks to the members of Dr. Ma’s group for their help in this project and also for their friendship. Special thanks to Dr. Ki Ho Park, Dr. Pei-hui Lin, the experimental data of the TRIC-A project and Dr. Zehua Bian, Dr. Qiang Wang, and Dr. Hua Zhu for the MG53 project. I would like to thank my committee members, Dr. Jill Rafael-Fortney, Dr. Hua Zhu, and Dr. Jian-Qiu Wu, who provided valuable guidance and feedback for this thesis. Thanks also to the Ohio State Biochemistry Program for the kind guidance and support. Thanks to Dr. Brian Foster for his review and suggestions for this thesis. Finally, I would like to thank my wonderful wife, Jing Tan, for the constant love, encouragement, and support during my Ph.D. study. Thanks also to all of my family, especially to my parents, Zhijian Zhou and Fengyun Zheng, for their great support and unconditional love and trust. iv Vita 2009................................................................B.S. Northwest University, Xi’an, China 2011-2012 ......................................................Graduate Fellowship, UMDNJ/Rutgers, New Brunswick, NJ 2012-Present ..................................................Graduate Research Associate, Department of Surgery, the Ohio State University, Columbus, OH Publications 1. Adesanya T, Russell, M, Park KH, Zhou X, Sermersheim M, Gumpper K, Koenig S, Tan T, Whitson B, Janssen P, Lincoln J, Zhu H, Ma J. MG53 protein protects aortic valve interstitial cells from membrane injury and fibrocalcific remodeling. J Am Heart Assoc. 2019. 2. Wang Z, Chen K, Han Y, Zhu H, Zhou X, Tan T, Zeng J, Zhang J, Liu Y and Li Y. Irisin Protects Heart Against Ischemia-Reperfusion Injury Through a SOD2- Dependent Mitochondria Mechanism. Journal of cardiovascular pharmacology. 2018. vi 3. Fan Z, Xu Z, Niu H, Gao N, Guan Y, Li C, Dang Y, Cui X, Liu XL, Duan Y, Li H, Zhou X, Lin PH, Ma J and Guan J. An Injectable Oxygen Release System to Augment Cell Survival and Promote Cardiac Repair Following Myocardial Infarction. Scientific reports. 2018;8:1371. 4. Elbaz M, Ahirwar D, Xiaoli Z, Zhou X, Lustberg M, Nasser MW, Shilo K and Ganju RK. TRPV2 is a novel biomarker and therapeutic target in triple negative breast cancer. Oncotarget. 2018;9:33459. 5. Fan Z, Fu M, Xu Z, Zhang B, Li Z, Li H, Zhou X, Liu X, Duan Y, Lin PH, Duann P, Xie X, Ma J, Liu Z and Guan J. Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction. Biomacromolecules. 2017;18:2820-2829. 6. Yao Y, Zhang B, Zhu H, Li H, Han Y, Chen K, Wang Z, Zeng J, Liu Y, Zhou X and Wang X. MG53 permeates through blood-brain barrier to protect ischemic brain injury. Oncotarget. 2016;7:22474. 7. Li H, Duann P, Lin PH, Zhao L, Fan Z, Tan T, Zhou X, Sun M, Fu M, Orange M, Sermersheim M, Ma H, He D, Steinberg S, Higgins R, Zhu H, John E, Zeng C, Guan J, e Ma J. Modulation of wound healing and scar formation by MG53- mediated cell membrane repair. Journal of Biological Chemistry, 2015. 290, 24592- 24603. vii 8. Ma H, Liu J, Bian Z, Cui Y, Zhou X, Zhou X, Zhang B, Adesanya TM, Yi F, Park KH, Tan T, Chen Z and Zhu H. Effect of metabolic syndrome on mitsugumin 53 expression and function. PLoS One. 2015;10:e0124128. 9. Liu XY*, Zhou XY*, Hou JC, Zhu H, Wang Z, Liu JX and Zheng YQ. Ginsenoside Rd promotes neurogenesis in rat brain after transient focal cerebral ischemia via activation of PI3K/Akt pathway. Acta Pharmacol Sin. 2015;36:421-8. 10. Duann P, Li H, Lin P, Tan T, Wang Z, Chen K, Zhou X, Gumpper K, Zhu H, Ludwig T, Mohler PJ, Rovin B, Abraham WT, Zeng C and Ma J. MG53-mediated cell membrane repair protects against acute kidney injury. Sci Transl Med. 2015;7:279ra36. 11. Zhou X, Lin P, Yamazaki D, Park KH, Komazaki S, Chen SR, Takeshima H and Ma J. Trimeric intracellular cation channels and sarcoplasmic/endoplasmic reticulum calcium homeostasis. Circ Res. 2014;114:706-16.C 12. Park KH, Weisleder N, Zhou J, Gumpper K, Zhou X, Duann P, Ma J and Lin PH. Assessment of calcium sparks in intact skeletal muscle fibers. J Vis Exp. 2014:e50898. 13. Jia Y, Chen K, Lin P, Lieber G, Nishi M, Yan R, Wang Z, Yao Y, Li Y, Whitson BA, Duann P, Li H, Zhou X, Zhu H, Takeshima H, Hunter JC, McLeod RL, Weisleder N, Zeng C and Ma J. Treatment of acute lung injury by targeting MG53- mediated cell membrane repair. Nat Commun. 2014;5:4387. viii Fields of Study Major Field: Ohio State Biochemistry Program ix Table of Contents Abstract .............................................................................................................................. ii Acknowledgments ............................................................................................................ iv Vita .................................................................................................................................... vi Table of Contents .............................................................................................................. x List of Figures .................................................................................................................. xv Chapter 1. Introduction ................................................................................................... 1 Cardiac calcium signaling .......................................................................................... 1 Calcium signaling ................................................................................................... 1 Excitation-Contraction Coupling (ECC)................................................................. 2 Store-overload induced Ca2+ release (SOICR) ........................................................ 3 Regulation of excitation-contraction....................................................................... 4 Ryanodine Receptor (RyR) .......................................................................................
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