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Molecular Mechanisms and Regulation of Cold Sensing

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Molecular Mechanisms and Regulation of Cold Sensing Molecular mechanisms and regulation of cold sensing A dissertation submitted to the Division of Research and Advanced Studies Of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (Ph.D.) in the Neuroscience Graduate Program in the College of Medicine By Ignacio Sarria B.A. St. Thomas University, Miami, Florida 2006 October 2011 Dissertation Committee: Jianguo Gu, Ph.D., Advisor Steve Kleene, Ph.D., Committee Chair: Mark Baccei, Ph.D. Jun-Ming Zhang, M.D, Ph.D. David Richards, Ph.D. Sarria, I General Abstract TRPM8 is the principal sensor of cold temperatures in mammalian primary sensory neurons. Cold temperatures 28~8°C and the cooling compound menthol activate TRPM8. TRPM8 is expressed on nociceptive and non-nociceptive primary sensory neurons and mediates innocuous and painful cold sensations. Using calcium imaging, I examined menthol responses and role of protein kinases in two functionally distinct populations of cold-sensing DRGs that use TRPM8 receptors to convey innocuous (menthol-sensitive/capsaicin-insensitive, MS/CI) and noxious (menthol-sensitive/capsaicin-sensitive, MS/CS) cold sensation. PKC activation decreased menthol response in all neurons. MS/CI neurons had larger menthol responses with greater adaptation and adaptation was attenuated by blocking PKC and CaMKII. In contrast MS/CS neurons had smaller menthol responses with less adaptation that was not affected by blocking PKC or CaMKII. In both MS/CI and MS/CS neurons, menthol responses were not affected by PKA activation or inhibition. Taken together, these results suggest that TRPM8- mediated responses are different between non-nociceptive-like and nociceptive-like neurons (Chapter II). Calcium influx causes a feedback regulation of TRPM8 currents that when analyzed under whole-cell voltage-clamp exhibit a Ca2+-dependent functional downregulation with two distinctive phases, a shorter, faster acute desensitization and a prolonged tachyphylaxis. Using acutely dissociated rat DRGs I examined TRPM8 whole-cell currents while pharmacologically manipulating several intracellular targets. TRPM8 acute desensitization is caused by calmodulin and requires phosphatidylinositol 4,5-bisphosphate (PIP2). Conversely, tachyphylaxis is mediated by hydrolysis of PIP2 and activation of PKC/phosphatase 1,2A. Consequently, I set out to determine the mechanisms underlying the mentioned findings by studying inside-out 3 Sarria, I recordings of TRPM8 channels stably expressed in HEK 293 cells. PIP2 switches TRPM8 channel gating to a high open probability state with short closed times and Ca2+-calmodulin reverses the effect of PIP2, switching channel gating to a low open probability state with long closed times. Thus, through gating modulation, Ca2+-calmodulin provides a mechanism to rapidly regulate TRPM8 functions in the somatosensory system (Chapter III). It is not well understood how cooling temperatures have multiple sensory effects ranging from generating cooling or painful cold sensation to modifying sensory modalities like touch, itch and pain. With electrophysiology I studied how temperature modulates excitability in DRGs. Cooling temperatures differentially modify the excitability of non-nocicepetive and nociceptive neurons. Cold aborts repeated action potential firing in non-nociceptive neurons by increasing the voltage-dependent inactivation of TTXs Na+ channels and reducing A-type K+ currents. Cooling temperatures also inhibit IA in nociceptive-like neurons, which possessed TTXr Nav 1.8 channels, but these neurons largely retain or increase firing rate. Cold had less inhibition on TTXr Na+ channels, allowing nociceptive neurons to fire at painful cold temperatures. Like cold, IA blocker 4-AP reduced IA-K+ currents in TTXs and TTXr cells, but this led to higher spike frequency only in the latter. Finally, the molecular determinants for neuron excitability under cooling temperatures play a role in defining temperature threshold and ranges for which innocuous and noxious cold directly elicit impulses in nociceptive and non- nociceptive cold-sensing neurons respectively, providing a molecular mechanism for sensory distinction between innocuous and noxious cold stimuli (Chapter IV). 4 Sarria, I 5 Sarria, I Acknowledgments I would like to thank the following people: Advisor: I would like to deeply thank Dr.Gu for welcoming me in his lab and providing an encouraging scientific niche where I could thrive. You have been truly a very good mentor and I will certainly miss our almost daily discussions. Thank you for introducing me to the world of electrophysiology and for the valuable training and teaching you offered me throughout graduate school. Committee members: Thank you Dr. Steve Kleene, Dr. Mark Baccei, Dr. Jun-Ming Zhang, and Dr. David Richards, for your help and guidance. Lab members: Myeounghoon Cha, and Jennifer Ling. Thank you for your help, friendship, and tenderness Jennifer. You made looking at DRGs exciting. Friends: Balu, Freddy, and Kostas. Good friends make the best buffer from grad school’s hardships. Girlfriend: Thank you Megan for all your support, patience and levity. Stacking the freezer with food has saved me this last month. Parents: Thank you for being so wonderful throughout the years. Since I was a child, you have fostered me and my inquisitive nature with patience and affection. I remember you never discouraged me, even when I asked a hundred questions in our trips to San Jose. Thanks to you I became an older kid who still likes asking the what, why, and how of things; I just do it a lab now. You are simply the best parents a son could ever have and I dedicate this to you. 6 Sarria, I Table of Contents Page GENERAL ABSTRACT………………………………………………………………..............iii ACKNOWLEDGEMENTS…….………………….…...…………………………................…vi TABLE OF CONTENTS……………….……………………………………………...........…vii LIST OFTABLES AND FIGURES……….………………………………...…………............ix CHAPTER 1: General Introduction.…………...…………………………………….............12 CHAPTER 2: TRPM8-mediated responses and adaptation are different in nociceptive-like vs. nonnociceptive-like neurons: role of protein kinase .............…...……………………………………………….....................24 Abstract…..………........……...................................................…...…..………………...25 Introduction………...........................................................................................................26 Materials and Methods……...….........…..................…….......……………………….....29 Results.............………............………………………………………………..................33 Discussion ..……...........….…………………………………………………..…............39 Figures……………………...…...........…….…………......………………………..........43 Notes to Chapter2…..……….......…………………………...…………...…...................53 CHAPTER 3: TRPM8 acute desensitization is mediated by Calmodulin and requires PIP2: Distinction from Tachyphylaxis ..........................................54 Abstract………………….……………………………………......................................…55 Introduction…............................…………………………………………………………56 Materials and Methods....………………........................………………………………...60 Results…………………………........................………………………………………....64 Discussion.....…………………………………….......................………………………..72 7 Sarria, I Figures………..................................................…………………………………………77 Notes to Chapter 3……...…..............…………………………………….............……..92 CHAPTER 4: Cold differentially modifies sensory neuron action potential firing properties: Contribution to sensory distinction between innocuous and noxious cold......................................................................93 Abstract………….........................……………………………………………………..…94 Introduction…………….........................…………...……………………………………96 Materials and Methods………........................…..……………………………………...100 Results……………………........................……..……………………………………....105 Discussion...…………........................…………………………………………………..116 Tables and Figures…........................………………………………………………...….121 Notes to Chapter 4..........................….…….………………………...………………….135 CHAPTER 5: Summary............................................................................................................136 Figures……….................................................…………………………………………143 REFERENCES..........................................................................................................................146 8 Sarria, I List of tables and figures Page CHAPTER 1 CHAPTER 2 Figure 2.1. Responses to menthol, capsaicin and AIT in dorsal root ganglion neurons of rats........................…............…......……...………....…........................................43 Figure 2.2. Menthol responses in menthol-sensitive/capsaicin-insensitive and menthol-sensitive/capsaicin-sensitive neurons following prolonged menthol application......45 Figure 2.3. Recovery after menthol-induced adaptation in menthol-sensitive/capsaicin-insensitive and menthol-sensitive/capsaicin sensitive neurons..46 Figure 2.4. Responses to multiple brief applications of menthol..........…….….........……….47 Figure 2.5. Effect of PKC activator PDBu on menthol responses..........…..…....…..……….48 Figure 2.6. Lack of effect by PKA activators on menthol responses..........…......…..……….50 Figure 2.7. Effect of protein kinase inhibitors on menthol responses in MS/CI and MS/CS neurons..............................................................51 CHAPTER 3 Figure 3.1. Menthol-and
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