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Nicholas P Kinnear Phd Thesis AN INVESTIGATION OF NAADP-DEPENDENT CA² SIGNALLING MECHANISMS IN ARTERIAL SMOOTH MUSCLE ⁺ Nicholas P. Kinnear A Thesis Submitted for the Degree of PhD at the University of St. Andrews 2007 Full metadata for this item is available in Research@StAndrews:FullText at: http://research-repository.st-andrews.ac.uk/ Please use this identifier to cite or link to this item: http://hdl.handle.net/10023/364 This item is protected by original copyright This item is licensed under a Creative Commons License An investigation on NAADP- dependent Ca2+ signalling mechanisms in arterial smooth muscle Nicholas Patrick Kinnear A thesis submitted to the University of St Andrews for the degree of Doctor of Philosophy School of Biology University of St Andrews January 2007 Declarations I, Nicholas Patrick Kinnear, hereby certify that this thesis, which is approximately 73,000 words in length, has been written by me, that it is the record of work carried out by me and that it has not been submitted in any previous application for a higher degree. Date: Signature of candidate: I was admitted as a research student in October 2001 and as a candidate for the degree of PhD in October 2002; the higher study for which this is a record was carried out in the University of St Andrews between 2001 and 2006. Date: Signature of candidate: I hereby certify that the candidate has fulfilled the conditions of the Resolution and Regulations appropriate for the degree of PhD in the University of St Andrews and that the candidate is qualified to submit this thesis in application for that degree. Date: Signature of supervisor: In submitting this thesis to the University of St Andrews I understand that I am giving permission for it to be made available for use in accordance with the regulations of the University Library for the time being in force, subject to any copyright vested in the work, not being affected thereby. I also understand that the title and abstract will be published, and that a copy of the work may be made and supplied to any bona fide library or research worker. Date: Signature of candidate: I confirm that the experiments described in this thesis were performed by me and me alone, with the one exception of those experiments highlighted in Chapter 3 which were performed in association with Dr. Francois-Xavier Boittin during my initial training in the use of the whole-cell patch clamp technique. Date: Signature of candidate: i Acknowledgements There are so many people who deserve thanks and I am really sorry to anyone I miss out! Firstly I would like to thank Dr. Mark Evans for giving me this opportunity and for everything you have done for me over the course of my PhD. It has been a great journey for me and your support and encouragement have helped me get to the end. To everyone else in the Evans group, starting with Chris and Jill. Thanks for helping me with my constant queries, along with your endless help, advice with my thesis and your technical expertise in the lab. You guys have been great to work with. To the newer members of the group, Elisa and Pete, cheers for putting up with my rants and grumpiness while I have been writing up. It comes to us all, I promise!! (Mocha cheesecake definitely helps in the dark times) Thanks also to everyone who has helped me with technical support and advice in the Bute and the BMS over the course of my work, especially Dr. Francois Boittin for his patience while I learned to patch. Grant Churchill, Justyn Thomas and everyone else that I worked with during my time in Oxford. For the help in the lab and making me feel so welcome I thank you guys so much, I loved every minute. It really is amazing how much binding can be achieved in the Rose and Crown! Thanks to Madras Rugby club and everyone involved with it, thanks for the distraction, the banter, the friendship and the camaraderie during the past 4 years. If I couldn’t have vented on the paddock I think I might have gone nuts! To all the members of the Clan, I can’t fit you all in here individually but thanks to every single one of you for the interest, kindness and endless encouragement you have given me. Finally, the most important people through all of this: Beccy, my time in St Andrews has been the hardest, but thanks to you, some of the happiest times I’ve ever known, you give me the belief in myself that I sometimes lack and for that I have to say “Cheers Dr. Dollface!” Mum, Dad, Chris, Shona Ann, Jamie and Luke. The greatest family and the best influence anyone could ask for. I could never put into words just what you have done for me over the years but I think you have an idea of how much I appreciate everything. You have supported and encouraged me in everything I’ve ever done and for that I am eternally grateful. This work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC). ii Abstract Previous investigations on pulmonary artery smooth muscle cells have shown that nicotinic acid adenine dinucleotide diphosphate (NAADP) evokes highly localised intracellular Ca2+ bursts by mobilising thapsigargin-insensitive Ca2+ stores. Such localised Ca2+ signals may initiate global Ca2+ waves and contraction of the myocytes through the recruitment of ryanodine receptors (RyR) located on the sarcoplasmic reticulum (SR) via Ca2+-induced Ca2+- release (CICR). In this thesis I have shown that NAADP evokes localised Ca2+ signals through the mobilisation of a bafilomycin A1-sensitive, lysosome- related Ca2+ store. Lysosomal Ca2+ stores facilitate this process by colocalising with a subpopulation of RyRs on the surface of the SR to comprise a highly specialised trigger zone for Ca2+ signalling by NAADP. I have also shown that the proposed trigger zone for NAADP-dependent Ca2+ signalling may be formed between lysosomes and clusters of RyR subtype 3 (RyR3) located in close proximity to one another in the perinuclear region of cells. Localised Ca2+ bursts generated by NAADP-dependent Ca2+ release from acidic Ca2+ stores and subsequent CICR via RyR3 on the SR may then amplify Ca2+ bursts into a propagating Ca2+ signal by recruiting clusters of RyR subtype 2 (RyR2) located in the perinuclear and extra-perinuclear regions of the cell. The presence of this trigger zone may explain, in part, why Ca2+ bursts by NAADP induce, in an all-or-none manner, global Ca2+ signals by CICR via RyRs on the SR. Consitent with a role for NAADP and lysosomes as a discrete and agonist- specific Ca2+ signalling pathway utilised by vasoconstrictors, I have shown that endothelin-1 (ET-1), but not phenylephrine or prostaglandin-F2, mobilises Ca2+ stores by NAADP, and that ET-1 initiates Ca2+ signalling by NAADP in a receptor subtype-specific manner through the activation of ETB receptors. These findings further advance our understanding of how that spatial organisation of discrete, organellar Ca2+ stores underpin the generation of differential Ca2+ signalling patterns by different Ca2+-mobilising messengers. iii Table of contents Title page Declaration i Acknowledgements ii Abstract iii Table of contents iv Chapter 1: Introduction 1 1.1 The circulatory system 1 1.1.1 Arteries 1 1.1.2 Capillaries and the microcirculation 2 1.1.3 The endothelium 2 1.1.4 Veins 4 1.2 Smooth muscle 4 1.2.1 Excitation-contraction coupling in smooth muscle 5 1.2.2 The role of K+ channels in the regulation of smooth muscle membrane potential 6 1.2.2.1 Voltage activated K+ channels 7 1.2.2.2 Large conductance Ca2+-activated K+ channels 8 1.2.2.3 Inward rectifier K+ channels 10 1.2.2.4 ATP-sensitive K+ channels 11 1.2.2.5 Two-pore domain K+ channels 12 1.2.3 A role for Cl- channels in modulation of smooth muscle membrane potential? 13 1.2.3.1 Ca2+-activated Cl- channels 13 1.2.3.2 Volume sensitive Cl- channels 14 1.2.4 Ca2+ influx pathways in vascular smooth muscle 15 1.2.5 The plasma membrane and Ca2+ extrusion mechanisms 18 1.3 Intracellular Ca2+ stores in arterial smooth muscle 20 1.3.1 The sarcoplasmic reticulum 20 1.3.2 Mechanism of smooth muscle contraction 25 1.3.3 Ca2+ sensitisation of smooth muscle 26 1.4 Ca2+ mobilising second messengers 30 2+ 1.4.1 Ca mobilisation by IP3 30 1.4.1.1 Synthesis and metabolism of IP3 30 1.4.1.2 Cells express different IP3Rs, each with varying sensitivities to IP3 31 2+ 1.4.1.3 Regulation of IP3Rs by cytoplasmic Ca and IP3 33 1.5 Ca2+ mobilization by pyridine nucleotides 33 1.5.1 An historical overview 33 1.5.2 Ca2+ mobilization by cADPR via ryanodine receptors 38 1.5.3 cADPR does not bind directly to ryanodine receptors 41 1.5.4 cADPR-dependent Ca2+ signalling in vascular smooth muscle 42 1.5.5 Ca2+ mobilization by cADPR in arterial smooth muscle 44 1.5.6 cADPR and vasoconstriction 44 1.5.6.1 Does cADPR mediate vasoconstrictor-induced iv sarcoplasmic reticulum Ca2+ release in arterial smooth muscle? 44 1.5.6.2 Does cADPR facilitate Ca2+-induced Ca2+-release in response to voltage-gated Ca2+ influx? 45 1.5.7 Ca2+-dependent vasodilation by cADPR 46 1.5.8 NAADP as a Ca2+ mobilizing messenger 49 1.5.8.1 Ca2+ mobilization by NAADP occurs from a non-ER/SR Ca2+ store 49 1.5.8.2 Inactivation of NAADP-induced Ca2+ release 52 1.5.8.3 The NAADP receptor 54 2+ 1.5.8.4 Co-operative Ca signalling between NAADP, IP3 and cADPR 54 1.5.8.5 Acidic Ca2+ stores, the source of NAADP-mediated Ca2+ signals? 55 1.5.8.6 A role for NAADP-dependent Ca2+ signalling in vascular smooth muscle 59 1.6 The pulmonary circulation 60 1.6.1 Pulmonary blood flow 60 1.6.2 Pulmonary arteries 61 1.6.3 Pulmonary veins 61 1.6.4 Pulmonary capillaries 62 1.6.5 Nervous innervation 62 1.7 Hypoxic pulmonary
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