N-甲基-D-天冬氨酸受体(NMDAR)为谷氨酸介导的细胞间通讯提供了途径,以其在大脑中的作用而闻名,但在非神经元细胞中具有多种功能。其他人和我们先前发表的数据提供了离体证据,表明NMDAR调节血小板和红细胞(RBC)的产生。这里,我们总结了NMDAR的造血作用。在巨核细胞(血小板前体)和红系细胞中表达的NMDAR亚基的类型更常见于发育中的大脑,而不是成人的大脑。暗示营养功能。然而,类似于它们的神经元对应物,造血NMDARs作为离子通道,并且对钙离子(Ca2+)是可渗透的。阻断开放NMDAR(美金刚和MK-801)的抑制剂干扰原代培养中的巨核细胞成熟和前血小板形成。对前血小板形成的影响似乎涉及Ca2流入依赖性调节细胞骨架重塑。与正常巨核细胞相反,NMDAR在白血病Meg-01细胞中的作用从分化转移到增加增殖。NMDAR功能减退触发Meg-01细胞分化,偏向红细胞生成。潜在的机制涉及细胞内Ca2+稳态的变化,细胞应激途径,和造血转录因子在NMDAR抑制后从巨核细胞的优势转向红系调节因子。NMDAR平衡巨核细胞和红系细胞命运的能力表明受体参与了双潜能巨核细胞-红系祖细胞的水平。在人类红细胞前体和循环红细胞中,NMDAR调节细胞内Ca2+稳态。NMDAR活性支持早期成红细胞的存活,在成熟的红细胞中,NMDARs会影响细胞的水合状态,血红蛋白氧亲和力,和一氧化氮合酶活性。成熟红细胞中NMDAR的过度引用导致Ca2+过载,K+损失,红细胞脱水,和氧化应激,这可能有助于镰状细胞病的发病机理。总之,越来越多的证据表明,谷氨酸-NMDAR信号在成熟的不同阶段调节巨核细胞和红系细胞,正常细胞和病变细胞之间在NMDAR表达和功能方面出现了一些有趣的差异。NMDAR信号可能为血液病提供新的治疗机会,但在体内的适用性需要确认。
The N-methyl-D-aspartate receptor (NMDAR) provides a pathway for glutamate-mediated inter-cellular communication, best known for its role in the brain but with multiple examples of functionality in non-neuronal cells. Data previously published by others and us provided ex vivo evidence that NMDARs regulate platelet and red blood cell (RBC) production. Here, we summarize what is known about these hematopoietic roles of the NMDAR. Types of NMDAR subunits expressed in megakaryocytes (platelet precursors) and erythroid cells are more commonly found in the developing rather than adult brain, suggesting trophic functions. Nevertheless, similar to their neuronal counterparts, hematopoietic NMDARs function as ion channels, and are permeable to calcium ions (Ca2+). Inhibitors that block open NMDAR (memantine and MK-801) interfere with megakaryocytic maturation and proplatelet formation in primary culture. The effect on proplatelet formation appears to involve Ca2+ influx-dependent regulation of the cytoskeletal remodeling. In contrast to normal megakaryocytes, NMDAR effects in leukemic Meg-01 cells are diverted away from differentiation to increase proliferation. NMDAR hypofunction triggers differentiation of Meg-01 cells with the bias toward erythropoiesis. The underlying mechanism involves changes in the intracellular Ca2+ homeostasis, cell stress pathways, and hematopoietic transcription factors that upon NMDAR inhibition shift from the predominance of megakaryocytic toward erythroid regulators. This ability of NMDAR to balance both megakaryocytic and erythroid cell fates suggests receptor involvement at the level of a bipotential megakaryocyte-erythroid progenitor. In human erythroid precursors and circulating RBCs, NMDAR regulates intracellular Ca2+ homeostasis. NMDAR activity supports survival of early proerythroblasts, and in mature RBCs NMDARs impact cellular hydration state, hemoglobin oxygen affinity, and nitric oxide synthase activity. Overexcitation of NMDAR in mature RBCs leads to Ca2+ overload, K+ loss, RBC dehydration, and oxidative stress, which may contribute to the pathogenesis of sickle cell disease. In summary, there is growing evidence that glutamate-NMDAR signaling regulates megakaryocytic and erythroid cells at different stages of maturation, with some intriguing differences emerging in NMDAR expression and function between normal and diseased cells. NMDAR signaling may provide new therapeutic opportunities in hematological disease, but in vivo applicability needs to be confirmed.