Sigma受体是结合黄体酮和/或血红素以及几种不相关的异源物质/化学物质的非阿片/非苯环利定受体。它们存在于质膜和内质网膜中,线粒体,和核。直到最近,这些蛋白质的生物学/药理学主要集中在它们在大脑/视网膜神经元功能中的作用。然而,随着这些蛋白质在铁/血红素稳态中的意外作用的发现,该领域的最新进展。Sigma受体1(S1R)调节氧化应激相关转录因子NRF2并防止铁凋亡,铁诱导的细胞死亡过程。西格玛受体2(S2R),在结构上与S1R无关,与孕激素受体膜组分PGRMC1和PGRMC2的复合物。S2R,PGRMC1和PGRMC2独立或作为蛋白质-蛋白质复合物,引起多种影响,对铁/血红素稳态有深远的影响。这包括调节铁调节激素hepcidin的分泌,线粒体铁螯合酶活性的调节,催化铁掺入原卟啉IX形成血红素,将血红素与特定的血液蛋白结合,从而影响其生物活性和稳定性,和防止铁中毒。因此,S1R,S2R,PGRMC1和PGRMC2增强血色素沉着病和癌症的疾病进展。这些新发现将这一有趣的非传统孕激素受体带入了生物学和医学领域。
Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein-protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial
ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine.