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SALZER Isabella.Pdf Excitation of Rat Sympathetic Neurons via M1 Muscarinic Receptors Independently of Kv7 channels DOCTORAL THESIS AT THE MEDICAL UNIVERSITY OF VIENNA for obtaining the academic degree Doctor of Philosophy Submitted by Isabella Salzer, MD Supervisor Prof. Dr. Stefan Böhm ZENTRUM FÜR PHYSIOLOGIE UND PHARMAKOLOGIE, ABTEILUNG FÜR NEUROPHYSIOLOGIE UND -PHARMAKOLOGIE, Schwarzspanierstraße 17, 1090 Wien Vienna, 31. 1. 2014 Contents List of Figures ii List of Tables iii List of Abbreviations iv Acknowledgements vii Abstract viii Zusammenfassung ix 1 Introduction 1 1.1 Basics of nerve cell communication .......................... 1 1.1.1 TheRestingMembranePotential....................... 1 1.1.2 Theactionpotential.............................. 2 1.1.3 Synaptic transmission . ............................ 2 1.2Thesympatheticnervoussystem........................... 4 1.3 Acetylcholine and its receptors ............................ 4 1.3.1 Acetylcholine .................................. 4 1.3.2 Nicotinic acetylcholine receptors ....................... 5 1.3.3 Muscarinic acetylcholine receptors ...................... 5 1.4Typesofionchannels................................. 8 1.4.1 Ligand-gatedionchannels........................... 10 1.4.2 Voltage-gatedionchannels........................... 10 1.4.3 Ionchannelsneithergatedbyligandsnorvoltage.............. 13 1.5 Modulation of ion channels by G-protein coupled receptors ............. 19 1.5.1 Modulation of ion channels by depletion of phosphatidylinositol 4,5 bis- phosphate .................................... 21 1.5.2 Modulation of ion channels via release of calcium from intracellular stores 22 1.5.3 Modulation of ion channels via activation of protein kinase C ....... 23 1.6 Aim of the project . .................................. 23 2 Results 25 3 Discussion 65 Bibliography 79 i List of Figures 1.1 Nicotinic acteylcholine receptors ............................ 6 1.2 Muscarinic acetylcholine receptors .......................... 9 1.3 Kv7voltage-gatedpotassiumchannels........................ 17 1.4 Ca2+-activated Cl− channels.............................. 20 1.5 Modulation of ion channels by Gαq-coupled GPCRs ................ 22 ii List of Tables 1.1 Muscarinic Acetylcholine Receptors .......................... 8 1.2Ligand-gatedionchannels............................... 11 1.3Voltage-gatedionchannels............................... 12 1.4Ionchannelsnotprimarilygatedbyaligandorvoltage............... 13 1.5 Calcium-activated chloride channels . ....................... 21 1.6ProteinkinaseCisoforms............................... 24 iii List of Abbreviations 5-HT serotonin ACh acetylcholine ADP adenosine diphosphate AMP adenosine monophosphate AMPA α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid ANO anoctamin ASIC acid sensing ion channels ATP adenosine triphosphate B2 bradykinin B2 receptor B2R bradykinin B2 receptor BK big-conductance K+ channel 2+ Cav voltage-gated Ca channel CaCC Ca2+-activated Cl− channel CaM calmodulin cAMP cyclic adenosine monophosphate CFTR cystic fibrosis transmembrane conductance regulator cGMP cyclic guanosine monophosphate ClC chloride channels CLCA Ca2+-activated Cl− channel family CNG cyclic nucleotide gated channels CNS central nervous system DAG diacylglycerol DIDS 5-isothiocyanato-2-[2-(4-isothiocyanato-2-sulfophenyl)ethenyl]benzene-1-sulfonic acid DRG dorsal root ganglion e. p. p. end plate potential ELKS active zone protein ENaC epithelial sodium channel EPSP excitatory postsynaptic potential ER endoplasmatic reticulum iv List of Tables GABA γ-aminobutyric acid GDP guanosine diphosphate GPCR G-protein coupled receptor GRK2 G-protein coupled receptor kinase 2 GTP guanosine triphosphate IK intermediate-conductance K+ channel + IKR rapid delayed rectifying K current + IKS slow delayed rectifying K current IP3 inositol 1,4,5 trisphosphate IP3R inositol 1,4,5 trisphosphate receptor IV curve current-voltage relation + K2P two-pore K channels 2+ + KCa Ca -activated K channels + Kir inward rectifier K channels + Kv voltage-gated K channels KCNQ gene name of Kv7 channels M1-M5 muscarinic M1 -M5 receptors M1R muscarinic M1 receptor M1-4 membrane spanning helices of nAChRs mAChR muscarinic acetylcholine receptor MT3 mamba toxin 3 MT7 mamba toxin 7 NA noradrenaline + Navi voltage-insensitive Na leak channel + Nav voltage-gated Na channel nAChR nicotinic acetylcholine receptor NCS1 neuronal calcium sensor 1 NKCC1 Na+-K+-2 Cl− co-transporter NMDA N-methyl-D-aspartate NSF N-ethylmaleimide-sensitive factor OxoM oxotremorine methiodite + + − pNa/pK /pCl Na /K /Cl permeability PE phorbolester PIP2 phosphatitylinositol 4,5 bisphosphate v List of Tables PKC protein kinase C PLCβ phospholipase C β PMA phorbol-12-myristate-13-acetate PNS peripheral nervous system PTX pertussis toxin Rab3 Ras GTPase superfamily RCBM regulatory calmodulin-binding motif RCK regulating conductance of K+ RIM Rab3-interacting molecule/ Unc-10 RIM-BP RIM binding protein RyR ryanodine receptor S1-6 membrane spanning domains of Kv SCG superior cervical ganglion SITS 2-[2-(4-acetamido-2-sulfophenyl)ethenyl]-4-isothiocyanatobenzene-1-sulfonic acid SK small-conductance K+ channel SM-protein family Sec1/Munc18 protein family SNAP-25 synaptosome associated protein of 25 kDa SNARE Soluble NSF-attachment protein receptor SUR1 sulfonyl urea receptor 1 TM transmembrane domain TMD1-8 transmembrane domain 1-8 of CaCCs TMEM16 transmembrane proteins with unknown function 16 TRP transient receptor potential cation channels TTX tetrodotoxin VRAC volume regulated anion channel ZAC zinc activated channel vi Acknowledgements I want to thank Stefan Böhm for believing in me and letting me continue to work in his lab - even though, I tend to mess up projects. I think he is an exceptionally good supervisor, who always tries to find the best solution for all PhD students - not just his students. I want to thank him for making a PhD students life easier at the MUW. I want to thank Klaus Schicker: for teaching me how to use electrophysiology, for discussing theoretical aspects of the technique with me, for discussing all kinds of things with me and thereby teaching me how to be critical, for teaching me how to use a computer properly, for showing me how to maintain a functional electrophysiological setup, for drinking coffee with me and finally for sharing my affinity for Songs from the "Erste Allgemeine Verunsicherung". I want to thank Xaver König for being very patient with everyone in the lab (including me, of course) and repairing or fixing everything that needs to be fixed. You are responsible for transforming "Schrotti" into "Flotti". I want to thank Sylvia Pagler for reducing the bureaucracy load to an absolute minimum and always taking care of us. I want to thank Gabi Gaupmann for taking over primary cell culture from me. This saved me a lot of time, which I could spend on experimenting and writing. I want to thank Hend, Manu, Marco, Jae-Won, Verena, Dagmar and everyone else in the lab for creating such a nice work environment - Thank you for making my job cool! I want to thank the FWF for funding the PhD-Program CCHD. Without proper funding, none of us would be able to work. Finally, I want to thank my family for accepting me the way I am, for accepting my moods and for accepting when I have no time - once again. I want to thank my parents for letting me choose my career. I want to thank them for supporting me, no matter what. vii Abstract Slow ganglionic transmission relies on activation of muscarinic M1 receptors and the subsequent inhibition of Kv7 channels. However, the activation threshold for Kv7 channels lies at more pos- itive potentials than the actually measured membrane voltage. Hence, inhibiting a non-active channel is unlikely to underlie M1 receptor mediated slow EPSPs. Additionally, the muscarinic agonist oxotremorine M (OxoM) triggered depolarizations in sympathetic neurons of the rat, but not in all investigated neurons. On the other hand, OxoM mediated Kv7 channel inhibition in all tested neurons. Changing intra- and extracellular chloride concentrations revealed an influence of chloride on both in OxoM-triggered depolarizations as well as noradrenaline release. Two non-selective chloride channel inhibitors niflumic acid and 2-[2-(4-acetamido-2-sulfophenyl)ethenyl]-4-isothiocyanato- benzene-1-sulfonic acid (SITS) reduced depolarizations and noradrenalin release evoked by OxoM, but left OxoM-mediated Kv7 channel inhibition unaltered. A slow rising inward current at -65 mV induced by OxoM was inhibited by selective antagonists of TMEM16A (anoctamin-1) and TMEM16B (anoctamin-2), who is responsible for Ca2+-activated Cl−currents. In addition, these selective inhibitors strongly reduced OxoM-evoked noradrenalin release from neuronal cultures of rat sympathetic ganglia. Activation of M1 receptors triggers formation of diacylglycerol, which activates protein kinase C (PKC). By using different kinds of PKC inhibitors, a dependence of OxoM-induced depolariza- tions and noradrenaline release from rat sympathetic neurons on classical PKCs was revealed. However, neither M-currents nor their inhibition via M1 receptors was influenced by PKC inhi- bition. Taken together, this study shows that slow cholinergic transmission is dependent on activation 2+ − of Ca -activated Cl channels in addition to being mediated by inhibition of Kv7 channels. Additionally, this pathway involves activity of PKC. viii Zusammenfassung Die langsame Komponente der synaptischen Übertragung in sympathischen Ganglien wird durch Aktivierung von
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