Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3:
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| 100 | 1 | |a Stephan, Gabriele |d 1988- |e Verfasser |0 (DE-588)1172088705 |4 aut | |
| 245 | 1 | 0 | |a Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 |c vorgelegt von Gabriele Stephan |
| 264 | 1 | |a Leipzig |c [2018] | |
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Datensatz im Suchindex
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| adam_text | INDEX
SUMMARY........................................................................................................................................................I
ZUSAMMENFASSUNG....................................................................................................................................
V
1
INTRODUCTION..........................................................................................................................................1
1.1 PURINERGIC
RECEPTORS....................................................................................................................1
1.2 P2X
RECEPTORS..............................................................................................................................
1
1.2.1 MOLECULAR STRUCTURE, ATP BINDING AND GATING MECHANISM
.........................................
2
1.2.2 FUNCTIONAL ASPECTS OF P 2 X R S
..........................................................................................
4
1.3 THE P2X3
RECEPTOR......................................................................................................................5
1.3.1 STRUCTURE, GATING MECHANISM AND ION PERMEATION PATHWAYS
....................................
5
1.3.2 AFFERENT SIGNALING OF THE P 2 X 3 R
.....................................................................................
7
1.4 THE DEG/ENAC FAMILY OF ION
CHANNELS...............................................................................10
1.5 ACID SENSING ION CHANNELS
(ASICS)......................................................................................
10
1.5.1 ARCHITECTURE AND PH-DEPENDENT GATING MECHANISM
................................................
11
1.5.2 MODULATION AND PAIN-RELEVANT SIGNALING OF A S IC S
....................................................13
1.6 STRUCTURAL AND FUNCTIONAL SIMILARITIES BETWEEN P2X3 AND A S IC S
.....................................
15
1.7 AIM OF THE
THESIS.........................................................................................................................16
1.8
PUBLICATIONS...............................................................................................................................
18
1.8.1 RELATIONSHIP OF THE
PUBLICATIONS...................................................................................
18
1.9
REFERENCES..................................................................................................................................20
2 INTER-SUBUNIT DISULFIDE LOCKING OF THE HUMAN P2X3 RECEPTOR ELUCIDATES
ECTODOMAIN
MOVEMENTS ASSOCIATED WITH CHANNEL
GATING...................................................................................30
2.1
ABSTRACT......................................................................................................................................31
2.2
INTRODUCTION...............................................................................................................................31
2.3 MATERIAL AND
METHODS.............................................................................................................
33
2.3.1 HOMOLOGY MODELING OF THE HP2X3R AND M D S S
.......................................................33
2.3.2 SITE-DIRECTED
MUTAGENESIS............................................................................................
33
2.3.3 CULTURING OF HEK293 CELLS AND TRANSIENT TRANSFECTION
.............................................
34
2.3.4 WHOLE-CELL PATCH CLAMP RECORDINGS
.............................................................................
34
2.3.5 DATA
ANALYSIS...................................................................................................................
35
2.4 RESULTS
...............
36
2.4.1 HOMOLOGY MODELING PREDICTS INTER-SUBUNIT INTERACTIONS OF THE
ECTODOMAIN
INTERFACES THAT REARRANGE DURING GATING OF THE HP 2X 3R
...........................................................36
2.4.2 DISULFIDE LOCKING OF INTER-SUBUNIT RESIDUE PAIRS E57C/T263C AND
E112C/R198C
BLOCKS HP2X3R CHANNEL
FUNCTION..................................................................................................38
2.4.3 DOUBLE MUTANT CYCLE ANALYSIS SUPPORTS THE PAIRWISE ENERGETIC
COUPLING OF
E57/T263 AND E 112/R
198.............................................................................................................
40
2.4.4 THE E112/R198 INTERACTION IS ELECTROSTATIC IN
NATURE...............................................42
2.5
DISCUSSION.................................................................................................................................
45
2.6
ACKNOWLEDGEMENT...................................................................................................................
48
2.7 SUPPLEMENTARY M
ATERIAL........................................................................................................
49
2.8
REFERENCES................................................................................................................................
50
3 THE ASIC3/P2X3 COGNATE RECEPTOR IS A PAIN-RELEVANT AND LIGAND-GATED
CATIONIC
CHANNEL........................................................................................................................................
55
3.1
ABSTRACT......................................................................................................................................
56
3.2
INTRODUCTION...............................................................................................................................56
3.3 MATERIAL AND
METHODS.............................................................................................................
57
3.3.1 PLASMID PREPARATION AND SITE-DIRECTED
MUTAGENESIS...............................................57
3.3.2 CULTURING OF CHO CELLS AND TRANSFECTION
PROCEDURES...............................................58
3.3.3 CULTURING OF RAT DORSAL ROOT GANGLION
CELLS...................................................................58
3.3.4 WHOLE-CELL PATCH-CLAMP RECORDING AND DRUG
APPLICATION.........................................58
3.3.5 IMMUNOFLUORESCENCE AND CONFOCAL LASER SCANNING
MICROSCOPY...........................59
3.3.6 CO-IMMUNOPRECIPITATION AND WESTERN BLOT
................................................................
60
3.3.7 EXPRESSION OF THE RASIC3 AND RP2X3 SUBUNITS IN OOCYTES
....................................
60
3.3.8 TWO-ELECTRODE VOLTAGE-CLAMP
ELECTROPHYSIOLOGY......................................................61
3.3.9 BIOCHEMICAL ANALYSIS OF SUBUNIT OLIGOMERISATION IN OCYTES
....................................
61
3.3.10 MEASUREMENT OF MECHANICAL
HYPERALGESIA...............................................................
62
3.3.11 DATA
ANALYSIS...................................................................................................................62
3.4
RESULTS.......................................................................................................................................
64
3.4.1 ACTIVATION OF RECOMBINANT ASIC AND P2X3RS IN CHO CELLS
64
3.4.2 INTERACTION BETWEEN THE TWO RECOMBINANT RECEPTORS
...............................................
67
3.4.3 INTERACTION BETWEEN THE TWO NATIVE
RECEPTORS........................................................... 76
3.4.4 INTERACTION BETWEEN THE TWO RECEPTORS IN OOCYTES
....................................................
79
3.4.5 HYPERALGESIA INDUCED BY ACIDIFICATION AND PURINERGIC STIMULATION
.......................
82
3.5
DISCUSSION.................................................................................................................................
84
3.6
ACKNOWLEDGEMENT...................................................................................................................
87
3.7 SUPPLEMENTARY M
ATERIAL........................................................................................................
88
3.8
REFERENCES................................................................................................................................96
4
APPENDIX.........................................................................................................................................100
4.1
SELBSSTAENDIGKEITSERKLAERUNG...................................................................................................
100
4.2 PUBLICATIONS AND CONFERENCE
CONTRIBUTIONS.....................................................................
101
4.3 CURRICULUM
VITAE....................................................................................................................
102
4.4
ABBREVIATIONS.........................................................................................................................
103
4.5 ACKNOWLEDGEMENT /
DANKSAGUNG......................................................................................105
|
| adam_txt |
INDEX
SUMMARY.I
ZUSAMMENFASSUNG.
V
1
INTRODUCTION.1
1.1 PURINERGIC
RECEPTORS.1
1.2 P2X
RECEPTORS.
1
1.2.1 MOLECULAR STRUCTURE, ATP BINDING AND GATING MECHANISM
.
2
1.2.2 FUNCTIONAL ASPECTS OF P 2 X R S
.
4
1.3 THE P2X3
RECEPTOR.5
1.3.1 STRUCTURE, GATING MECHANISM AND ION PERMEATION PATHWAYS
.
5
1.3.2 AFFERENT SIGNALING OF THE P 2 X 3 R
.
7
1.4 THE DEG/ENAC FAMILY OF ION
CHANNELS.10
1.5 ACID SENSING ION CHANNELS
(ASICS).
10
1.5.1 ARCHITECTURE AND PH-DEPENDENT GATING MECHANISM
.
11
1.5.2 MODULATION AND PAIN-RELEVANT SIGNALING OF A S IC S
.13
1.6 STRUCTURAL AND FUNCTIONAL SIMILARITIES BETWEEN P2X3 AND A S IC S
.
15
1.7 AIM OF THE
THESIS.16
1.8
PUBLICATIONS.
18
1.8.1 RELATIONSHIP OF THE
PUBLICATIONS.
18
1.9
REFERENCES.20
2 INTER-SUBUNIT DISULFIDE LOCKING OF THE HUMAN P2X3 RECEPTOR ELUCIDATES
ECTODOMAIN
MOVEMENTS ASSOCIATED WITH CHANNEL
GATING.30
2.1
ABSTRACT.31
2.2
INTRODUCTION.31
2.3 MATERIAL AND
METHODS.
33
2.3.1 HOMOLOGY MODELING OF THE HP2X3R AND M D S S
.33
2.3.2 SITE-DIRECTED
MUTAGENESIS.
33
2.3.3 CULTURING OF HEK293 CELLS AND TRANSIENT TRANSFECTION
.
34
2.3.4 WHOLE-CELL PATCH CLAMP RECORDINGS
.
34
2.3.5 DATA
ANALYSIS.
35
2.4 RESULTS
.
36
2.4.1 HOMOLOGY MODELING PREDICTS INTER-SUBUNIT INTERACTIONS OF THE
ECTODOMAIN
INTERFACES THAT REARRANGE DURING GATING OF THE HP 2X 3R
.36
2.4.2 DISULFIDE LOCKING OF INTER-SUBUNIT RESIDUE PAIRS E57C/T263C AND
E112C/R198C
BLOCKS HP2X3R CHANNEL
FUNCTION.38
2.4.3 DOUBLE MUTANT CYCLE ANALYSIS SUPPORTS THE PAIRWISE ENERGETIC
COUPLING OF
E57/T263 AND E 112/R
198.
40
2.4.4 THE E112/R198 INTERACTION IS ELECTROSTATIC IN
NATURE.42
2.5
DISCUSSION.
45
2.6
ACKNOWLEDGEMENT.
48
2.7 SUPPLEMENTARY M
ATERIAL.
49
2.8
REFERENCES.
50
3 THE ASIC3/P2X3 COGNATE RECEPTOR IS A PAIN-RELEVANT AND LIGAND-GATED
CATIONIC
CHANNEL.
55
3.1
ABSTRACT.
56
3.2
INTRODUCTION.56
3.3 MATERIAL AND
METHODS.
57
3.3.1 PLASMID PREPARATION AND SITE-DIRECTED
MUTAGENESIS.57
3.3.2 CULTURING OF CHO CELLS AND TRANSFECTION
PROCEDURES.58
3.3.3 CULTURING OF RAT DORSAL ROOT GANGLION
CELLS.58
3.3.4 WHOLE-CELL PATCH-CLAMP RECORDING AND DRUG
APPLICATION.58
3.3.5 IMMUNOFLUORESCENCE AND CONFOCAL LASER SCANNING
MICROSCOPY.59
3.3.6 CO-IMMUNOPRECIPITATION AND WESTERN BLOT
.
60
3.3.7 EXPRESSION OF THE RASIC3 AND RP2X3 SUBUNITS IN OOCYTES
.
60
3.3.8 TWO-ELECTRODE VOLTAGE-CLAMP
ELECTROPHYSIOLOGY.61
3.3.9 BIOCHEMICAL ANALYSIS OF SUBUNIT OLIGOMERISATION IN OCYTES
.
61
3.3.10 MEASUREMENT OF MECHANICAL
HYPERALGESIA.
62
3.3.11 DATA
ANALYSIS.62
3.4
RESULTS.
64
3.4.1 ACTIVATION OF RECOMBINANT ASIC AND P2X3RS IN CHO CELLS
64
3.4.2 INTERACTION BETWEEN THE TWO RECOMBINANT RECEPTORS
.
67
3.4.3 INTERACTION BETWEEN THE TWO NATIVE
RECEPTORS. 76
3.4.4 INTERACTION BETWEEN THE TWO RECEPTORS IN OOCYTES
.
79
3.4.5 HYPERALGESIA INDUCED BY ACIDIFICATION AND PURINERGIC STIMULATION
.
82
3.5
DISCUSSION.
84
3.6
ACKNOWLEDGEMENT.
87
3.7 SUPPLEMENTARY M
ATERIAL.
88
3.8
REFERENCES.96
4
APPENDIX.100
4.1
SELBSSTAENDIGKEITSERKLAERUNG.
100
4.2 PUBLICATIONS AND CONFERENCE
CONTRIBUTIONS.
101
4.3 CURRICULUM
VITAE.
102
4.4
ABBREVIATIONS.
103
4.5 ACKNOWLEDGEMENT /
DANKSAGUNG.105 |
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| spelling | Stephan, Gabriele 1988- Verfasser (DE-588)1172088705 aut Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 vorgelegt von Gabriele Stephan Leipzig [2018] 1 CD-ROM (IX, 105 Blätter) Illustrationen 12 cm txt rdacontent c rdamedia cd rdacarrier Dissertation Universität Leipzig 2018 (DE-588)4113937-9 Hochschulschrift gnd-content (DE-588)4139307-7 CD-ROM gnd-carrier B:DE-101 application/pdf http://d-nb.info/1172850887/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=032143977&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis Textdatei PDF |
| spellingShingle | Stephan, Gabriele 1988- Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 |
| subject_GND | (DE-588)4113937-9 (DE-588)4139307-7 |
| title | Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 |
| title_auth | Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 |
| title_exact_search | Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 |
| title_exact_search_txtP | Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 |
| title_full | Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 vorgelegt von Gabriele Stephan |
| title_fullStr | Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 vorgelegt von Gabriele Stephan |
| title_full_unstemmed | Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 vorgelegt von Gabriele Stephan |
| title_short | Extracellular structures influencing the gating mechanism of the P2X3 receptor and its interaction with the acid sensing ion channel (ASIC) 3 |
| title_sort | extracellular structures influencing the gating mechanism of the p2x3 receptor and its interaction with the acid sensing ion channel asic 3 |
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