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ABSTRACT

Contents

Abbreviations 14

Chapter 1. G Protein-coupled Receptor Signaling and Cross-talk : Achieving Rapidity and Specificity. 15

1-1. Introduction. 15

1-2. The established paradigm of GPCR signaling 17

1-3. New paradigms of GPCR signaling 19

1-3-1. Concept of microdomain as a functional signaling platform 19

1-3-2. Cross-talk of GPCRs 22

1-3-2-1. Cross-talk between GPCRs 23

1-3-2-2. Cross-talk between GPCR and other signaling pathways 28

1-4. Concluding remarks 35

1-5. References 38

Chapter 2. Materials and Methods. 44

2-1. Antibodies. 44

2-2. Plasmids. 45

2-3. RNA interference and RT-PCR. 45

2-4. In situ hybridization. 46

2-5. Northern blot. 47

2-6. Western blot and immunoprecipitation. 47

2-7. Preparation of adrenal medullary chromaffin cells. 48

2-8. PC12 cell culture. 49

2-9. Measurement of [Ca2+]i and its imaging.(이미지참조) 49

2-10. Measurement of cAMP contents. 50

2-11. Measurement of IP₃. 51

2-12. Measurement of [³H]NE secretion. 52

2-13. Measurement of membrane potential. 53

2-14. Mn2+ quenching of fura-2 fluorescence.(이미지참조) 53

2-15. Amperometry. 53

2-16. HPLC. 54

2-17. Confocal microscopy and image analysis. 54

2-18. Immunogold electron microscopy. 55

2-19. Detergent solubilization and sucrose gradient fractionation. 56

2-20. Statistical analysis. 57

Chapter 3. Sensitization of Epidermal Growth Factor (EGF)-induced Signaling by Bradykinin Is Mediated by c-Src : Implications for a Role of Lipid Microdomains. 58

3-1. Introduction. 58

3-2. Results. 60

3-2-1. Sensitization of EGF-induced [Ca2+]i increase by BK.(이미지참조) 60

3-2-2. Involvement of EGFR. 61

3-2-3. Role of c-Src in the BK-induced sensitization. 62

3-2-4. Induction of EGF-mediated exocytosis by BK. 64

3-2-5. Signaling events in the detergent-resistant membrane (DRM) fraction. 64

3-2-6. Involvement of Src-dependent EGFR phosphorylation. 65

3-2-7. Effects of cellular cholesterol depletion and add-back. 66

3-3. Discussion. 67

3-4. References. 88

Chapter 4. Junctional Membrane Inositol 1,4,5-trisphosphate Receptor (IP₃R) Complex Coordinates Sensitization of the Silent EGF-induced Ca2+ Signaling.(이미지참조) 91

4-1. Introduction. 91

4-2. Results. 94

4-2-1. Involvement of PKA is involved in sensitization of the silent EGF-induced Ca2+ signaling and exocytosis.(이미지참조) 94

4-2-2. IP₃R1 is required for the sensitization. 96

4-2-3. EGFR, PKA, and yotiao (AKAP9) comprise a macromolecular signaling complex with IP₃R1. 98

4-2-4. IP₃R1 is phosphorylated in response to BK stimulation in a PKA-dependent manner. 99

4-2-5. AKAP signaling complex is required for the PKA-dependent phosphorylation of IP₃R1 by BK and promotes the sensitization process. 100

4-3. Discussion. 101

4-4. References. 126

Chapter 5. Coupling of L-type Voltage-Sensitive Calcium Channels (VSCCL) to P2X₂ Purinoceptors in PC12 Cells.(이미지참조) 129

5-1. Introduction. 129

5-2. Results. 130

5-2-1. Effects of Ca2+ channel inhibitors on P2X-mediated [Ca2+]i increase and secretion.(이미지참조) 130

5-2-2. P2X-mediated [Ca2+]i rise in depolarized cells.(이미지참조) 132

5-2-3. Inhibition of P2X-mediated cation entry by Ca2+ channel blockers.(이미지참조) 132

5-2-4. P2X receptor subtypes are coupled to VSCCL.(이미지참조) 134

5-2-5. Activation of VSCCs by membrane depolarization via Na+ influx through P2X₂ purinoceptors.(이미지참조) 135

5-3. Discussion. 138

5-4. References. 153

SUMMARY(KOREAN) 155

Appendix 159

Curriculum vitae 167

Acknowledgements 173

LIST OF TABLES

Table 4-1. BK increases cAMP contents via activation of B₂ receptors. 109

Table 4-2. Distribution of distances between EGFR at the PM and IP₃R1 at Ca2+ stores in rat adrenal medullary chromaffin cells(이미지참조) 110

LIST OF FIGURES

Chapter 1. 12

Fig. 1-1. Effector molecules regulated by different Gα- and Gβγ-subunits.(이미지참조) 36

Fig. 1-2. Schematic model of arising paradigms in GPCR signaling. 37

Chapter 3. 12

Fig. 3-1. Proposed model for the possible role of lipid raft in signal transduction. 74

Fig. 3-2. BK sensitizes EGF-induced [Ca2+]i increase.(이미지참조) 75

Fig. 3-3. Sensitization of the EGF-induced [Ca2+]i increase.(이미지참조) 76

Fig. 3-4. PLC-dependent Ca2+ release is induced by EGF after BK treatment.(이미지참조) 78

Fig. 3-5. Involvement of EGFR in the sensitization. 79

Fig. 3-6. Involvement of Src kinase in the sensitization. 80

Fig. 3-7. Src-mediated sensitization of EGF-evoked exocytosis. 82

Fig. 3-8. Phosphorylation and translocation events occur in the DRM fraction. 83

Fig. 3-9. Src-dependent phosphorylation of EGFR on Tyr-845 is critical to the sensitization. 84

Fig. 3-10. Effects of cellular cholesterol depletion and add-back on the Sensitization. 85

Fig. 3-11. EGF-induced ERK phosphorylation is not affected by BK. 87

Chapter 4. 12

Fig. 4-1. IP₃R as a signal integrator. 111

Fig. 4-2. Sensitization of the functionally silent EGF-induced [Ca2+]i increase and exocytosis by BK in rat adrenal chromaffin cells.(이미지참조) 112

Fig. 4-3. Involvement of PKA in the sensitization process. 114

Fig. 4-4. Expression and subcellular localization of IP₃R subtypes. 116

Fig. 4-5. IP₃R1 is required for the sensitization. 118

Fig. 4-6. Yotiao (AKAP9), PKA, and EGFR comprise a macromolecular signaling complex with IP₃R1. 119

Fig. 4-7. Immunogold EM showing colocalization of EGFR and IP₃R1 in adrenal chromaffin cells. 120

Fig. 4-8. Immunoconfocal microscopy images showing colocalization of endogenous EGFR and IP₃R1 in adrenal chromaffin cells. 121

Fig. 4-9. Phosphorylation of IP₃R1 upon application of BK. 123

Fig. 4-10. AKAP signaling complex facilitates BK-induced phosphorylation of IP₃R1 and the sensitization process. 124

Fig. 4-11. Suggested model for the sensitization of EGF-induced Ca2+ release and exocytosis by BK.(이미지참조) 125

Chapter 5 13

Fig. 5-1. P2 purinoceptors in PCl2 cells. 142

Fig. 5-2. VSCCs in PC12 cells. 143

Fig. 5-3. Effect of VSCC blockers on the ATP-, 2-MeSATP-, and UTP-induced responses in PC12 cells. 144

Fig. 5-4. Effect of 70 mM K+ pretreatment on the ATP-, 2-MeSATP-, and UTP-induced [Ca2+]i increase.(이미지참조) 145

Fig. 5-5. Effect of VSCC blockers on ATP-, 2-MeSATP-, and UTP-evoked [Ca2+]i increase after treatment with TG.(이미지참조) 146

Fig. 5-6. Effect of nifedipine on Mn2+ quenching and Ca2+ influx.(이미지참조) 147

Fig. 5-7. P2X receptor subtypes coupled to L-type VSCCs. 148

Fig. 5-8. ATP-, 2-MeSATP-, and UTP-induced depolarization measured with bisoxonol. 149

Fig. 5-9. Effect of nifedipine on the ATP- and 2-MeSATP-induced [Ca2+]i increase under Na+-free conditions.(이미지참조) 150

Fig. 5-10. Effect of 2-MeSATP and K+ on depolarization and [Ca2+]i rise.(이미지참조) 151

Fig. 5-11. Proposed model for the coupling of P2X₂ purinoceptors and VSCCL.(이미지참조) 152

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