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University of Nevada, Reno Mechanisms of Release, Metabolism And University of Nevada, Reno Mechanisms of release, metabolism and action of purines in the enteric and central nervous systems A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cellular and Molecular Pharmacology and Physiology by Leonie Durnin Violeta N. Mutafova-Yambolieva, M.D, Ph.D/Dissertation Advisor August 2013 © by Leonie Durnin 2013 All Rights Reserved THE GRADUATE SCHOOL We recommend that the dissertation prepared under our supervision by LEONIE DURNIN entitled Mechanisms of release, metabolism and action of purines in the enteric and central nervous systems be accepted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Violeta Mutafova-Yambolieva, MD,PhD, Advisor Kenton M. Sanders, Ph.D, Committee Member Sean M. Ward, Ph.D, Committee Member Brian A. Perrino, Ph.D, Committee Member Thomas Kidd, Ph.D, Graduate School Representative Marsha H. Read, Ph. D., Dean, Graduate School August, 2013 i Abstract It has been fifty years since the first descriptions of non-adrenergic non- cholinergic (NANC) neurotransmission were made in the gastrointestinal (GI) tract and more than forty years since it was discovered that NANC neurotransmission was mediated by a purine nucleotide. These influential advances in understanding neuroeffector mechanisms in smooth muscle led Dr. Geoffrey Burnstock to coin the terms ‘purinergic co-transmission’ and ‘purinergic nerves’. This led to an explosion of interest in purinergic mechanisms controlling the activity of various smooth muscle organs. While adenosine 5’-triphosphate (ATP) has traditionally been considered to be the purine nucleotide responsible for NANC responses, the last decade has uncovered important additional purinergic mechanisms controlling smooth muscle function. Based on the results obtained using extremely sensitive high-pressure liquid chromatography (HPLC) methodologies, nicotinamide adenine dinucleotide (NAD+) has emerged as a novel extracellular signaling factor released during stimulation of peripheral nerves and has a putative neurotransmitter or neuromodulator role. These original findings have significantly advanced our understanding in the field of purinergic signaling. There is substantial evidence that nerve stimulation-evoked release of NAD+ in smooth muscles originates from neural sources, however the complex organization of smooth muscle organs makes verification of vesicular NAD+ release a challenging task. Thus in Chapter 2 of this dissertation we utilized a single cell model to examine storage and release of NAD+ from vesicles in nerve-growth factor (NGF)-differentiated rat ii pheochromocytoma PC12 cells which phenotypically resemble sympathetic neurons. In this study we verified the presence of NAD+ in vesicles along with ATP and catecholamines (dopamine). Interestingly, we revealed differential mechanisms of release of these three substances from vesicles: release of NAD+ and dopamine required intact SNAP-25-mediated exocytosis whereas ATP was released largely via SNAP-25- independent mechanisms. These observations in conjunction with a previous finding demonstrating ω-conotoxin GVIA-insensitive ATP release in blood vessels led us to question the true identity of the NANC neurotransmitter in GI muscles where purinergic neurotransmission was first described. In the GI tract, purines released from inhibitory motor neurons elicit postsynaptic hyperpolarization transients (inhibitory junction potentials, IJPs) in circular smooth muscles causing relaxation. In the attempt to clarify which purines are involved in mediating gut relaxation we carried out a series of experiments in murine and primate colonic muscles comparing mechanisms of release, metabolism and action of extracellular purines. In Chapter 3 we demonstrated that electrical field stimulation (EFS) evoked release of NAD+ that was dependent on the level of nerve stimulation and was significantly attenuated by blockers of neural activity. We also demonstrated that postsynaptic hyperpolarizations to exogenous NAD+ were abolished by factors inhibiting the endogenous purine-mediated IJP. On the other hand, release and postsynaptic effects of ATP remained largely intact by inhibitors of enteric purine neurotransmission. Therefore our evidence suggests that NAD+ is a better candidate than ATP as the purinergic inhibitory motor transmitter in colons from humans and non-human primates. iii Extracellular nucleotidases in the gut degrade purines in the extracellular compartment. Rapid metabolism of ATP once released might explain the discrepancies between exogenous ATP and the endogenous enteric purine transmitter. In Chapter 4 we examined postjunctional effects of direct metabolites of ATP and NAD+, adenosine 5’- diphosphate (ADP) and ADP-ribose (ADPR), respectively, in colonic muscles. First, we demonstrated that these metabolites are produced very rapidly in murine and primate colons (within 1 sec). Next, we found that membrane hyperpolarizations to ADPR, but not to ADP, mimicked the pharmacology of endogenous purine response; this is the first study demonstrating a bioactive role of ADPR in enteric smooth muscles. Our evidence indicates that rapid metabolism cannot explain the failure of ATP to match the endogenous transmitter in colon. Moreover our evidence suggests that multiple purines might contribute to enteric inhibitory responses produced during NANC neurotransmission. Thus purinergic inhibitory regulation of enteric smooth muscle is more complex than originally believed. EFS is a common approach for stimulating neural activity however it often fails to differentiate the precise sources of released molecules. For example, during EFS substances could be released from neuronal cell bodies or axons or from non-neuronal sources such as glia. In Chapter 5 we attempted to clarify the sites of release of ATP and NAD+ in GI smooth muscles by utilizing an alternative approach to stimulate purine release. Here we chemically activated the neuronal ligand-gated ion channel receptors, nicotinic acetylcholine receptors and serotonin 5-HT3 receptors, which are localized on cell bodies and dendrites of inhibitory motor neurons. We demonstrated that the release of ATP and NAD+ upon activation of these receptors originated from different sites iv within neurons and via different mechanisms. The release of NAD+ appeared to originate exclusively from nerve terminals and was abolished by neural inhibitors. However the release of ATP remained intact in the presence of neural inhibitors suggesting that ATP release may have originated primarily from the nerve cell bodies. Therefore in agreement with our previous studies release of NAD+ in the gut occurs by mechanisms consistent for a neurotransmitter. With the strong evidence supporting NAD+ as an enteric inhibitory neurotransmitter we also wanted to determine if NAD+ fulfills neurotransmitter criteria in the central nervous system (CNS). In Chapter 6 we examined release, metabolism and postjunctional effects of NAD+ in the rat brain. We demonstrated that in isolated rat forebrain synaptosomes NAD+ is released by mechanisms requiring intact vesicle exocytosis machinery. We also found that localized application of NAD+ (and ADPR) elicited Ca2+ transients in cultured cortical neurons suggesting that endogenous NAD+ could participate in neuronal-neuronal communication in the brain. Finally, we demonstrated that mechanisms involved in terminating the extracellular action of NAD+ exist in the brain. This is the first study suggesting that NAD+ qualifies as a putative neurotransmitter in the CNS. In summary, the work described in this dissertation provides novel information regarding the role of NAD+/ADPR in the enteric and central nervous systems. NAD+/ADPR qualify as enteric inhibitory motor neurotransmitters regulating colonic smooth muscle contractility. In addition, NAD+/ADPR may participate in neurotransmission in the CNS. Our findings are significant not only to further our understanding of complex purinergic mechanisms regulating central and enteric nervous v system functions but also afford the opportunity for selectively targeting the NAD+/ADPR system for the therapeutic treatment of pathological conditions resulting from altered purinergic signaling. vi Acknowledgements First, I would like to express my sincere thanks to my advisor Dr. Violeta Mutafova-Yambolieva for her wonderful guidance, insight and patience throughout my graduate studies at the University of Nevada. She has been a fantastic supervisor who has taught me so much throughout my time in her lab. I feel extremely lucky to have been afforded this opportunity to work in her laboratory and I am grateful for everything she has helped me with to get where I am today. Her enthuasism for science has truly made this journey a very enjoyable experience. Thank you! I would also like express my thanks to Dr. Sean Ward not only for his help and guidance over the years, but also for giving me the chance to come to Reno as an undergraduate student to gain experience in the research environment. It was this opportunity that inspired me to climb higher and pursue this Ph.D. Sincere thanks to the other members of my advisory committee, Dr. Kenton Sanders, Dr. Brian Perrino and Dr. Thomas Kidd. They have always been supportive and have always found time in their busy schedules to give me advice, for which I am extremely grateful. I would also like to thank everyone in the department of Physiology and the Cellular and Molecular
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