Prossnitz Eric R
Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States.
J Steroid Biochem Mol Biol. 2018 Feb;176:73-81. doi: 10.1016/j.jsbmb.2017.03.005. Epub 2017 Mar 8.
The (patho)physiology of estrogen and its receptors is complex. It is therefore not surprising that therapeutic approaches targeting this hormone include stimulation of its activity through supplementation with either the hormone itself or natural or synthetic agonists, inhibition of its activity through the use of antagonists or inhibitors of its synthesis, and tissue-selective modulation of its activity with biased ligands. The physiology of this hormone is further complicated by the existence of at least three receptors, the classical nuclear estrogen receptors α and β (ERα and ERβ), and the 7-transmembrane G protein-coupled estrogen receptor (GPER/GPR30), with overlapping but distinct pharmacologic profiles, particularly of anti-estrogenic ligands. GPER-selective ligands, as well as GPER knockout mice, have greatly aided our understanding of the physiological roles of GPER. Such ligands have revealed that GPER activation mediates many of the rapid cellular signaling events (including Ca mobilization, ERK and PI3K/Akt activation) associated with estrogen activity, as opposed to the nuclear ERs that are traditionally described to function as ligand-induced transcriptional factors. Many of the salutary effects of estrogen throughout the body are reproduced by the GPER-selective agonist G-1, which, owing to its minimal effects on reproductive tissues, can be considered a non-feminizing estrogenic compound, and thus of potential therapeutic use in both women and men. On the contrary, until recently GPER-selective antagonists had predominantly found preclinical application in cancer models where estrogen stimulates cell growth and survival. This viewpoint changed recently with the discovery that GPER is associated with aging, particularly that of the cardiovascular system, where the GPER antagonist G36 reduced hypertension and GPER deficiency prevented cardiac fibrosis and vascular dysfunction with age, through the downregulation of Nox1 and as a consequence superoxide production. Thus, similar to the classical ERs, both agonists and antagonists of GPER may be of therapeutic benefit depending on the disease or condition to be treated.
雌激素及其受体的（病理）生理学较为复杂。因此，针对这种激素的治疗方法包括通过补充激素本身、天然或合成激动剂来刺激其活性，通过使用拮抗剂或合成抑制剂来抑制其活性，以及使用偏向性配体对其活性进行组织选择性调节，也就不足为奇了。这种激素的生理学因至少存在三种受体而进一步复杂化，即经典的核雌激素受体α和β（ERα和ERβ），以及7跨膜G蛋白偶联雌激素受体（GPER/GPR30），它们具有重叠但不同的药理学特征，尤其是抗雌激素配体。GPER选择性配体以及GPER基因敲除小鼠极大地帮助我们理解了GPER的生理作用。此类配体已表明，与传统上被描述为配体诱导转录因子的核雌激素受体不同，GPER激活介导了许多与雌激素活性相关的快速细胞信号转导事件（包括钙动员、ERK和PI3K/Akt激活）。GPER选择性激动剂G-1重现了雌激素在全身的许多有益作用，由于其对生殖组织的影响极小，可被视为一种非雌性化的雌激素化合物，因此在女性和男性中都具有潜在的治疗用途。相反，直到最近，GPER选择性拮抗剂主要在雌激素刺激细胞生长和存活的癌症模型中得到临床前应用。最近这一观点发生了变化，因为发现GPER与衰老有关，特别是与心血管系统的衰老有关，在心血管系统中，GPER拮抗剂G36可降低高血压，GPER缺乏可通过下调Nox1从而减少超氧化物生成来预防随年龄增长出现的心脏纤维化和血管功能障碍。因此，与经典雌激素受体类似，根据所治疗的疾病或病症，GPER的激动剂和拮抗剂都可能具有治疗益处。
