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Vergleichende Funktionale Untersuchungen Des Hitze

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Vergleichende Funktionale Untersuchungen Des Hitze 0 Vergleichende funktionale Untersuchungen des Hitze-Capsaicin-Rezeptors (TRPV1) und des Kälte-Menthol-Rezeptors (TRPM8) in rekombinanten und nativen Zellsystemen (verwendete Spezies: Mensch, Ratte und Maus) Dissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften der Fakultät für Biologie der Ruhr-Universität Bochum vorgelegt von Hans-Jörg Behrendt aus Dortmund angefertigt am Lehrstuhl für Zellphysiologie, Prof. Dr. Dr. Dr. H. Hatt Bochum, 2004 1 Abkürzungen:........................................................................................................................................................ 5 1. EINLEITUNG............................................................................................................ 7 1.1. Sensorik und Schmerz................................................................................................................................. 7 1.1.1. Ionenkanäle und Rezeptoren ................................................................................................................. 9 1.1.2. Capsaicin und Menthol, historisch-pharmakologisch ....................................................................... 10 1.1.2.1. Capsaicin ....................................................................................................................................... 10 1.1.2.2. Menthol ......................................................................................................................................... 12 1.2. TRP-Kanäle................................................................................................................................................ 13 1.2.1. Funktionen............................................................................................................................................. 13 1.2.2. Klassifizierung....................................................................................................................................... 13 1.2.3. Ionenkanal-Eigenschaften und Aktivierungsmechanismen.............................................................. 14 1.2.4. Der Botenstoff Ca2+............................................................................................................................... 15 1.2.5. Thermo-TRP-Kanäle............................................................................................................................ 15 1.2.6. Der Hitze-Vanilloid-Rezeptor (TRPV1/VR1)..................................................................................... 16 1.2.6.1. Eigenschaften des Ionenkanals...................................................................................................... 17 1.2.6.2. Expressionsmuster......................................................................................................................... 17 1.2.6.3. Auswirkungen der Aktivierung..................................................................................................... 18 1.2.6.4. Antagonisten und die putative Bindestelle .................................................................................... 19 1.2.7. Der Kälte-Menthol-Rezeptor (TRPM8)..............................................................................................21 1.2.7.1. Expressionsmuster......................................................................................................................... 22 1.2.7.2. Eigenschaften des Ionenkanals...................................................................................................... 22 1.2.7.3. Auswirkungen der Aktivierung des TRPM8................................................................................. 22 1.3. Aufgabenstellung ....................................................................................................................................... 23 2. MATERIAL UND METHODEN ............................................................................... 25 2.1. Chemikalien, Enzyme und Medien .......................................................................................................... 25 2.1.1. Duft- und Aromastoffe ......................................................................................................................... 26 2.1.1.1. Reinsubstanzen.............................................................................................................................. 26 2.1.1.2. Aromamischungen......................................................................................................................... 26 2.1.2. Medien und Puffer ................................................................................................................................ 27 2.2. Bakterienstämme ....................................................................................................................................... 27 2 2.3. Molekularbiologische Methoden .............................................................................................................. 28 2.3.1. Polymerase-Kettenreaktion (PCR)...................................................................................................... 28 2.3.2. Agarose-Gelelektrophorese.................................................................................................................. 30 2.3.3. Isolierung von DNA aus Agarosegelen................................................................................................ 30 2.3.4. Aufreinigung von DNA aus PCR-Ansätzen........................................................................................ 30 2.3.5. Restriktion von DNA ............................................................................................................................ 30 2.3.6. Ligation von DNA ................................................................................................................................. 31 2.3.7. Isolierung von Plasmid-DNA über Anionenaustauschsäulen ........................................................... 31 2.3.8. Vektoren ................................................................................................................................................ 31 2.4. Software...................................................................................................................................................... 32 2.5. Statistik und Auswertungsparameter ...................................................................................................... 32 2.5.1. Statistik .................................................................................................................................................. 32 2.5.2. Auswertungsparameter ........................................................................................................................ 32 2.6. Zellkultur.................................................................................................................................................... 34 2.6.1. Kultivierung von HEK293- und CHO K1- Zellen ............................................................................. 34 2.6.2. Transfektionen ...................................................................................................................................... 35 2.7. DRG-Präparation ...................................................................................................................................... 36 2.7.1. Materialien ............................................................................................................................................ 36 2.7.2. Versuchsvorbereitung und Durchführung ......................................................................................... 37 2.8. FLIPR-Assay.............................................................................................................................................. 38 2.8.1. Aufbau des FLIPR-Systems................................................................................................................. 38 2.8.2. Versuchsdurchführung......................................................................................................................... 39 2.9. Ca2+-Imaging.............................................................................................................................................. 39 2.9.1. Material, Geräte und Software............................................................................................................ 40 2.10. Indirekte Immunfluoreszenz .................................................................................................................... 41 2.11. Tier-Schmerzmodelle in vivo..................................................................................................................... 42 2.11.1. Formalin-Modell .............................................................................................................................. 42 2.11.2. CFA-Modell ...................................................................................................................................... 43 3. ERGEBNISSE........................................................................................................ 45 3.1. Untersuchung des Vanilloid-Rezeptors 1 (VR1/TRPV1) ....................................................................... 45 3 3.1.1. Nachweis des TRPV1-Proteins via Immunfluoreszenz...................................................................... 45 3.1.2. Funktionale Charakterisierung des TRPV1......................................................................................
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