糖皮質激素受體
糖皮質激素受體(英語:Glucocorticoid receptor, GR),也稱為NR3C1(核受體亞家族3,C組,成員1),是皮質醇和其他糖皮質激素結合的受體。[8]
GR幾乎在身體的每個細胞中都有表達,並調節控制發育、新陳代謝和免疫反應的基因。因為受體基因以多種形式表達,它在身體的不同部位有許多不同的(多效性)作用。[9]
當糖皮質激素與GR結合時,其主要作用機制是調節基因轉錄。[10]未結合的受體存在於細胞的胞質溶膠中。受體與糖皮質激素結合後,受體-糖皮質激素複合物可以採取兩種途徑中的任一種。活化的GR複合物上調細胞核中抗炎蛋白的表達或抑制胞質溶膠中促炎蛋白的表達(通過阻止其他轉錄因子從細胞質轉移到細胞核中)。[11]
結構
編輯配體結合和反應
編輯在沒有激素的情況下,糖皮質激素受體位於與多種蛋白質複合的細胞質中,包括熱休克蛋白90(Hsp90)、熱休克蛋白70(Hsp70)和蛋白FKBP4(FK506結合蛋白4)。[16]內源性糖皮質激素皮質醇通過細胞膜擴散到細胞質中並與糖皮質激素受體結合,導致熱休克蛋白釋放。所得的活化形式GR具有兩種主要的作用機制,反式激活和反式阻遏,[17][18]如下所述。
轉錄激活
編輯一種直接的作用機制包括受體的同二聚化、通過主動轉運進入細胞核的易位以及與激活基因轉錄的特定 DNA 反應元件的結合。該作用機制被稱為轉錄激活。生物反應取決於細胞類型。
轉錄抑制
編輯在沒有激活的GR的情況下,其他轉錄因子如NF-κB或AP-1本身能夠反式激活靶基因。[19]
臨床意義
編輯GR在家族性糖皮質激素抵抗中異常。[20]
在中樞神經系統結構中,糖皮質激素受體作為神經內分泌整合的新代表引起了人們的興趣,作為內分泌影響的主要成分。該受體現在與對壓力源的短期和長期適應有關,可能對理解心理障礙至關重要,包括部分或所有亞型抑鬱症和創傷後應激障礙(PTSD)。[21]庫欣病典型的情緒失調等長期觀察結果證明了皮質類固醇在調節心理狀態中的作用。最近的進展表明在神經水平上與去甲腎上腺素和血清素的相互作用。[22][23]
在先兆子癇(一種常見於孕婦的高血壓疾病)中,可能靶向該蛋白質的miRNA序列水平在母親的血液中升高。相反,胎盤提高了含有這種miRNA的外泌體的水平,可能導致分子翻譯的抑制。該信息的臨床意義尚未明確。[24]
激動劑和拮抗劑
編輯相互作用
編輯糖皮質激素受體與以下物質相互作用:
- BAG1[27][28]
- CEBPB[29]
- CREBBP[30]
- DAP3[31]
- DAXX[32]
- HSP90AA1[31][33][34][35][36][37][38]
- HNRPU[39]
- MED1[40][41]
- MED14[41]
- 鹽皮質激素受體[42]
- NRIP1[40][43][44]
- NCOR1[45][46]
- NCOA1[40][47]
- NCOA2[40][48]
- NCOA3[40][49]
- POU2F1[50][51]
- RANBP9[52]
- RELA[52][53][54]
- SMAD3[55][56]
- SMARCD1[49]
- SMARCA4[49][57]
- STAT3[58][59]
- STAT5B[60]
- 硫氧還蛋白[61]
- TRIM28[62]
- YWHAH[63]
研究
編輯2022年6月28日發表的一篇論文表明,NR3C1可能是肌萎縮側索硬化(ALS)的潛在靶點之一。使用支持AI的生物靶點發現平台,發現NR3C1在CNS fALS和sALS中均被上調。通過靶點發現,可以進一步設計多種途徑和藥物來治療ALS。[64]
參考文獻
編輯- ^ 與糖皮質激素受體相關的疾病;在維基數據上查看/編輯參考.
- ^ 對Glucocorticoid receptor起作用的藥物;在維基數據上查看/編輯參考.
- ^ 對Nuclear receptor subfamily 3 group C member 1起作用的藥物;在維基數據上查看/編輯參考.
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