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系統識別號 U0026-0508201520311000
論文名稱(中文) 腦幹核區的G蛋白偶合受體經二聚體化後會促使高血壓的形成
論文名稱(英文) GPCR-Dimerization in Brainstem Nuclei Contributes to the Development of Hypertension
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 孫國清
研究生(英文) Gwo-Ching Sun
學號 S98971063
學位類別 博士
語文別 英文
論文頁數 136頁
口試委員 指導教授-曾清俊
共同指導教授-呂佩融
口試委員-張雅雯
召集委員-蕭宏昇
口試委員-劉秉彥
口試委員-何文譽
中文關鍵字 嗎啡受體  血壓  異源二聚體  孤立束核  一氧化氮 
英文關鍵字 mu opioid receptors  blood pressure  heterodimer  nucleus tractus solitarii  nitric oxide 
學科別分類
中文摘要 在生物體內中樞神經系統的延腦孤立束核,已知會有嗎啡接受器、內生性嗎啡前驅物,前腦啡黑細胞促素皮促素(pro-opiomelanocortin,POMC),及腦啡肽原(pro-enkephalin)的高度表現。這暗示,除了廣為人所熟知的止痛效果外,嗎啡可能有鲜為人知的心血管調控作用。相關研究指出,mu型嗎啡作用在孤立束核所造成的升血壓效果,會有劑量依賴(dose-dependent)的現象;即當劑量增加時其血壓也呈比例的增加。但其中詳細的分子作用機轉目前仍不清楚。在周邊感壓反射的主要投射中樞,孤立束核上,會有多種參與調控自主神經活性的神經傳導物質以及相關的接受器,這包含了同屬於抑制型G蛋白偶合受體的mu型嗎啡接受器以及alpha2a型腎上腺素接受器。先前活體外的實驗已證實mu型嗎啡接受器會與alpha2a型腎上腺素接受器形成所謂的異源二聚體 (heterodimer)。活化/抑制異源二聚體,會產生異於單一接受器的藥理學反應。相關的後續活體外研究指出:當mu型嗎啡接受器與alpha2a型腎上腺素接受器形成異源二聚體後,會造成alpha2a型腎上腺素接受器活性的減低。而許多研究已證實,中樞神經系統中的alpha2a型腎上腺素接受器活性降低,是造成血壓上升的原因之一。因此,我們假設中樞性高血壓的形成,有可能是在孤立束核上,mu型嗎啡接受器與alpha2a型腎上腺素接受器形成異源二聚體後,所造成alpha2a型腎上腺素接受器降血壓功能的活性降低所導致的。因此,首先,分別在正常血壓大鼠以及在高血壓大鼠的孤立束核上,先利用免疫螢光染色法去證實,mu型嗎啡接受器會與alpha2a型腎上腺素接受器有共同區域化現象(colocalization)。接著,再利用免疫共同沉澱法去證實,mu型嗎啡接受器會與alpha2a型腎上腺素接受器有相互作用(interaction)的現象。最後,再透過原位鄰位連接分析(in situ proximity ligation assay),直接去證實在孤立束核上,mu型嗎啡接受器確實會與alpha2a型腎上腺素接受器形成異源二聚體。接下來利用正常血壓大鼠,透過在孤立束核給予mu型嗎啡專一型作用劑(DAMGO)顯微注射,證實mu型嗎啡作用劑除了會造成血壓的上升外,還會誘使mu型嗎啡接受器與alpha2a型腎上腺素接受器異源二聚體的形成與異常的增加。相對的,在正常血壓大鼠孤立束核上,給予alpha2a型腎上腺素專一型作用劑(guanfacine)顯微注射,則並不會造成異源二聚體的形成。誘導異源二聚體形成與異常增加的mu型嗎啡專一型作用劑,在正常血壓大鼠孤立束核,顯微注射所造成血壓的上升,會合併相對應的一氧化氮產生減少。而這樣的現象,也可以在異源二聚體異常增多的高血壓大鼠孤立束上,觀察到相同的血壓上升,所呼應一氧化氮相對的減少。這樣的結果暗示著:原本用以透過一氧化氮生成增加,來降低血壓的alpha2a型腎上腺素接受器,在不管是內生性或是外因性所造成異位二聚體形成增加後,其alpha2a型腎上腺素接受器的活性確實是下降的。
依據上述的結果證實,在孤立束核中,異常增加的內生性mu型嗎啡會誘導mu型嗎啡接受器/alpha2a型腎上腺素接受器的異源二聚體形成增加,進而造成依賴一氧化氮生成來調控血壓的alpha2a型腎上腺素接受器活性的下降,因而造成高血壓的形成。
英文摘要 μ-Opioid receptors (μORs), pro-opiomelanocortin, and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTS). μ-Opioid agonists in the NTS cause dose-dependent increases in blood pressure (BP). However, the molecular mechanisms of this process remain unclear. Previous studies have revealed that the μORs heterodimerise with the α2A-adrenergic receptors (α2A-ARs) in vitro. We hypothesised that α2A-ARs lose their depressor effect when components of μOR/α2A-AR heterodimers in the NTS. Immunofluorescence staining revealed the colocalization of α2A-ARs and μORs in NTS neurons. A coimmunoprecipitation study also revealed an interaction between α2A-ARs and μORs. An in situ proximity ligation assay confirmed that μOR/α2A-AR heterodimers were present in the NTS. More endogenous endomorphin-1 and μOR/α2A-AR heterodimers were found in the NTS of hypertensive rats than in those of normotensive rats. Microinjection of the μOR agonist [D-Ala2, MePhe4, Gly5-ol]-enkephalin (DAMGO) into the NTS of normotensive rats promoted μOR/α2A-AR heterodimer-formations and BP elevation; however, the α2A-AR agonist guanfacine did not have the same effect. The nitric oxide (NO)-dependent BP-lowering effect of α2A-ARs was blunted as a result of greater μOR/α2A-AR heterodimer-formations in the NTS of hypertensive rats and DAMGO-treated normotensive rats. Our results suggest that inappropriate increases in endogenous μ-opioids in the NTS induce μOR/α2A-AR heterodimer-formations and reduce the NO-dependent depressor effect of α2A-ARs. Therefore, this process contributes to the pathogenesis of hypertension.
論文目次 目錄
摘要...............I
Abstract...............III誌謝..............IV
List of abbreviation.. ...........VI
目錄..............IX
List of figures ............XIII
List of tables.............XVII
Chapter 1
Introduction....01
Blood pressure regulation...........01
The nucleus of the solitary tract and Hypertension .......05
The role of NO in hypertension..........09
Effects of α2A-AR in central nerve system.......12
Effects of μOR in central nerve system........16
G protein-coupled receptor...........20
Functional consequences of heterodimerization......23
Altered heterodimerization leading to clinical disorder.....26
The implication of interaction of μOR and α2A-AR in the pathogenesis of hypertension.............30
Hypothesis and specific aims..........34
To confirm the heterodimerization of μORs and α2A-ARs in the NTS..34
To study the association of μORs/α2A-ARs heterodimers-formation and BP..35
To study the causes of μOR/α2A-AR heterodimer-formation in the NTS..36
To confirm the pathogenetic role of μOR/α2A-AR heterodimer- formation in the NTS on hypertension development........37
To investigate the mechanisms of μOR/α2A-AR heterodimer-mediated hypertension.............37
Chapter 2
Materials and methods.....39
Animals..............39
Intra-NTS microinjection...........39
Co-immunoprecipitation assay.........40
Immunofluorescence staining.........41
Fluorescence in situ α2A-AR and μOR proximity ligation assay....42
Measurement of NO in the NTS..........43
Immunoblotting analysis..........43
Statistical analysis............44
Results......45
μORs form heterodimers with α2A-ARs in the NTS.......45
Increases in μOR/α2A-AR heterodimers in the NTSs of hypertensive rats..48
Increases in endomorphin-1 in the NTSs of hypertensive rats.....52
Excessive μOR ligands induce heterodimer formations in the NTS....55
Microinjecting the μOR agonist DAMGO into the NTS of normotensive rats promoted μOR/α2A-AR heterodimer-formations......55
Endomorphin-1 blocking by the μOR antagonist CTAP reduced the number of μOR/α2A-AR heterodimers.....,.....58
μOR/α2A-AR heterodimer-formation is the cause rather than a consequence of hypertension.............61
Microinjecting the μOR agonist DAMGO into the NTS of WKY rats elevated BP as well as increased the number of μOR/α2A-AR heterodimers....61
μOR/α2A-AR heterodimer-formation is the cause rather than a consequence of hypertension.............64
CTAP pretreatment reduced the DAMGO-induced μOR/α2A-AR heterodimer-
formation and the BP-elevating effect........64
Intra-NTS CTAP microinjection markedly reduced BP and μOR/α2A-AR heterodimers in hypertensive SHRs.........67
Reducing BP in hypertensive rats had no effect on the number of μOR/α2A-AR heterodimers in the NTS..........70
Elevating BP in normotensive rats had no effect on the number of μOR/α2A-AR heterodimers in the NTS..........73
μOR/α2A-AR heterodimer-formation impaires the NO-dependent depressor effect of α2A-ARs in the NTS............76
The BP regulation of α2A-AR in the NTS is the NO-dependent depressor effect..76
The BP-lowering effect of α2A-ARs in the NTS is significantly attenuated in heterodimer-associated hypertension.........79
μOR/α2A-AR heterodimer-associated α2A-AR dysfunction is caused by the reduction of NO in the NTS...........82
DDAH1 provides a possible link between the pressor responses of the α2A-AR and μOR heterodimers and NO/NOS..........85
Discussion..............88
Chapter 3
Future perspectives............108
Conclusion.............112
References.............113
Publications lists.............135
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