糖皮质激素受体

糖皮质激素受体（英語：Glucocorticoid receptor, GR），也称为NR3C1（核受体亚家族3，C组，成员1），是皮质醇和其他糖皮质激素结合的受体。^[7]

糖皮質激素受體
已知的結構 PDB 直系同源搜索: PDBe RCSB PDBID列表 1M2Z、​1NHZ、​1P93、​3BQD、​3CLD、​3E7C、​3H52、​3K22、​3K23、​4CSJ、​4HN5、​4HN6、​4LSJ、​4MDD、​4P6W、​4P6X、​5CBY、​5CBX、​4UDC、​4UDD、​5CBZ、​5CC1、​5EMQ、​5EMC、​5EMP
識別號
别名	NR3C1；, GCCR, GCR, GCRST, GR, GRL, nuclear receptor subfamily 3 group C member 1, Glucocorticoid Receptor
外部ID	OMIM：138040 MGI：95824 HomoloGene：30960 GeneCards：NR3C1
相關疾病
glucocorticoid resistance^[1]
為以下藥物的標靶
布地奈德、​環索奈德、​丙酸氯倍他索、​皮質醇、​11-脱氧皮质酮、​去羥米松、​地塞米松、​difluprednate、​氟轻松、​氟欣諾能、​fluorometholone、​氟替卡松、​丙酸氟替卡松、​甲基培尼皮質醇、​泼尼松龙、​强的松、​RU28362、​去炎松、​曲安奈德、​倍他米松、​美服培酮^[2]
基因位置（人类） 染色体 5號染色體^[3] 基因座 5q31.3 起始 143,277,931 bp^[3] 终止 143,435,512 bp^[3]
基因位置（小鼠） 染色体 小鼠18号染色体^[4] 基因座 18 B3|18 21.09 cM 起始 39,543,598 bp^[4] 终止 39,652,474 bp^[4]
RNA表达模式
查阅更多表达数据
基因本體 分子功能 • steroid hormone binding • DNA结合 • sequence-specific DNA binding • DNA结合转录因子活性 • 鋅離子結合 • DNA-binding transcription activator activity, RNA polymerase II-specific • glucocorticoid receptor activity • nuclear receptor activity • 金屬離子結合 • RNA polymerase II cis-regulatory region sequence-specific DNA binding • steroid hormone receptor activity • steroid binding • 血浆蛋白结合 • lipid binding • RNA binding • SUMO binding • Hsp90 protein binding • DNA-binding transcription factor activity, RNA polymerase II-specific • protein kinase binding 細胞組分 • 細胞質 • 核质 • 线粒体基质 • 線粒體 • 细胞核 • 细胞骨架 • 纺锤体 • 微管组织中心 • 细胞质基质 • nuclear speck • 大分子复合体 生物學過程 • cellular response to steroid hormone stimulus • regulation of transcription, DNA-templated • glucocorticoid mediated signaling pathway • transcription by RNA polymerase II • transcription initiation from RNA polymerase II promoter • glucocorticoid receptor signaling pathway • 訊息傳遞 • steroid hormone mediated signaling pathway • 細胞週期 • 細胞分裂 • 细胞凋亡 • 染色体分离 • negative regulation of transcription by RNA polymerase II • transcription, DNA-templated • cellular response to dexamethasone stimulus • cellular response to transforming growth factor beta stimulus • positive regulation of transcription by RNA polymerase II • cellular response to glucocorticoid stimulus • chromatin organization • positive regulation of pri-miRNA transcription by RNA polymerase II Sources:Amigo / QuickGO
直系同源
物種	人類	小鼠
Entrez	2908	14815
Ensembl	ENSG00000113580	ENSMUSG00000024431
UniProt	P04150 Q3MSN4	P06537
mRNA​序列	NM_000176 ​NM_001018074 ​NM_001018075 ​NM_001018076 ​NM_001018077 ​NM_001020825 ​NM_001024094 ​NM_001204258 ​NM_001204259 ​NM_001204260 ​NM_001204261 ​NM_001204262 ​NM_001204263 ​NM_001204264 ​NM_001204265 ​NM_001364180 ​NM_001364181 ​NM_001364182 ​NM_001364183 ​NM_001364184 ​NM_001364185	NM_008173 ​NM_001361209 ​NM_001361210 ​NM_001361211 ​NM_001361212
蛋白序列	NP_000167 ​NP_001018084 ​NP_001018085 ​NP_001018086 ​NP_001018087 ​NP_001018661 ​NP_001019265 ​NP_001191187 ​NP_001191188 ​NP_001191189 ​NP_001191190 ​NP_001191191 ​NP_001191192 ​NP_001191193 ​NP_001191194 ​NP_001351109 ​NP_001351110 ​NP_001351111 ​NP_001351112 ​NP_001351113 ​NP_001351114 NP_000167.1 ​NP_001018084.1 ​NP_001018085.1 ​NP_001018086.1 ​NP_001018087.1 ​NP_001018661.1 ​NP_001019265.1 ​NP_001191187.1 ​NP_001191188.1 ​NP_001191189.1 ​NP_001191190.1 ​NP_001191191.1 ​NP_001191192.1 ​NP_001191193.1	NP_001348138 ​NP_001348139 ​NP_001348140 ​NP_001348141 ​NP_032199
基因位置​（UCSC）	Chr 5: 143.28 – 143.44 Mb	Chr 18: 39.54 – 39.65 Mb
PubMed​查找	^[5]	^[6]
維基數據
檢視/編輯人類 檢視/編輯小鼠

GR几乎在身体的每个细胞中都有表达，并调节控制发育、新陈代谢和免疫反应的基因。因为受体基因以多种形式表达，它在身体的不同部位有许多不同的（多效性）作用。^[8]

当糖皮质激素与GR结合时，其主要作用机制是调节基因转录。^[9]未结合的受体存在于细胞的胞质溶胶中。受体与糖皮质激素结合后，受体-糖皮质激素复合物可以采取两种途径中的任一种。活化的GR复合物上调细胞核中抗炎蛋白的表达或抑制胞质溶胶中促炎蛋白的表达（通过阻止其他转录因子从细胞质转移到细胞核中）。^[10]

在人体内，GR蛋白由位于5号染色体上的NR3C1基因编码。^[11][12]

结构

与其他类固醇受体一样，^[13]糖皮质激素受体在结构上是模块化的，^[14]并包含以下结构域（标记为A - F）：

• A/B - N端调控域
• C - DNA结合域（DBD）
• D - 铰链区
• E - 配体结合域（LBD）
• F - C端结构域

配体结合和反应

在没有激素的情况下，糖皮质激素受体位于与多种蛋白质复合的细胞质中，包括热休克蛋白90（Hsp90）、热休克蛋白70（Hsp70）和蛋白FKBP4（FK506结合蛋白4）。^[15]内源性糖皮质激素皮质醇通过细胞膜扩散到细胞质中并与糖皮质激素受体结合，导致热休克蛋白释放。所得的活化形式GR具有两种主要的作用机制，反式激活和反式阻遏，^[16][17]如下所述。

转录激活

一种直接的作用机制包括受体的同二聚化、通过主动转运进入细胞核的易位以及与激活基因转录的特定 DNA 反应元件的结合。该作用机制被称为转录激活。生物反应取决于细胞类型。

转录抑制

在没有激活的GR的情况下，其他转录因子如NF-κB或AP-1本身能够反式激活靶基因。^[18]

临床意义

GR在家族性糖皮质激素抵抗中异常。^[19]

在中枢神经系统结构中，糖皮质激素受体作为神经内分泌整合的新代表引起了人们的兴趣，作为内分泌影响的主要成分。该受体现在与对压力源的短期和长期适应有关，可能对理解心理障碍至关重要，包括部分或所有亚型抑郁症和创伤后应激障碍（PTSD）。^[20]库欣病典型的情绪失调等长期观察结果证明了皮质类固醇在调节心理状态中的作用。最近的进展表明在神经水平上与去甲肾上腺素和血清素的相互作用。^[21][22]

在先兆子痫（一种常见于孕妇的高血压疾病）中，可能靶向该蛋白质的miRNA序列水平在母亲的血液中升高。相反，胎盘提高了含有这种miRNA的外泌体的水平，可能导致分子翻译的抑制。该信息的临床意义尚未明确。^[23]

激动剂和拮抗剂

地塞米松和其他皮质类固醇是激动剂，^[24]而米非司酮和酮康唑是GR的拮抗剂。^[25]

相互作用

糖皮质激素受体与以下物质相互作用：

• BAG1^[26][27]
• CEBPB^[28]
• CREBBP^[29]
• DAP3^[30]
• DAXX^[31]
• HSP90AA1^{[30][32][33][34][35][36][37]}
• HNRPU^[38]
• MED1^[39][40]
• MED14^[40]
• 盐皮质激素受体^[41]
• NRIP1^[39][42][43]
• NCOR1^[44][45]
• NCOA1^[39][46]
• NCOA2^[39][47]
• NCOA3^[39][48]
• POU2F1^[49][50]
• RANBP9^[51]
• RELA^[51][52][53]
• SMAD3^[54][55]
• SMARCD1^[48]
• SMARCA4^[48][56]
• STAT3^[57][58]
• STAT5B^[59]
• 硫氧还蛋白^[60]
• TRIM28^[61]
• YWHAH^[62]

研究

2022年6月28日发表的一篇论文表明，NR3C1可能是肌萎缩侧索硬化（ALS）的潜在靶点之一。使用支持AI的生物靶点发现平台，发现NR3C1在CNS fALS和sALS中均被上调。通过靶点发现，可以进一步设计多种途径和药物来治疗ALS。^[63]

参考文献

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