Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, DF, 04510, Mexico.
Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA, 98195, USA.
Commun Biol. 2020 Nov 12;3(1):665. doi: 10.1038/s42003-020-01393-3.
N-methyl-D-aspartate receptors (NMDAR) are glutamate-gated calcium channels named after their artificial agonist. NMDAR are implicated in cell proliferation under normal and pathophysiological conditions. However, the role of NMDAR during mitosis has not yet been explored in individual cells. We found that neurotransmitter-evoked calcium entry via endogenous NMDAR in cortical astrocytes was transient during mitosis. The same occurred in HEK293 cells transfected with the NR1/NR2A subunits of NMDAR. This transient calcium entry during mitosis was due to phosphorylation of the first intracellular loop of NMDAR (S584 of NR1 and S580 of NR2A) by cyclin B/CDK1. Expression of phosphomimetic mutants resulted in transient calcium influx and enhanced NMDAR inactivation independent of the cell cycle phase. Phosphomimetic mutants increased entry of calcium in interphase and generated several alterations during mitosis: increased mitotic index, increased number of cells with lagging chromosomes and fragmentation of pericentriolar material. In summary, by controlling cytosolic calcium, NMDAR modulate mitosis and probably cell differentiation/proliferation. Our results suggest that phosphorylation of NMDAR by cyclin B/CDK1 during mitosis is required to preserve mitotic fidelity. Altering the modulation of the NMDAR by cyclin B/CDK1 may conduct to aneuploidy and cancer.
N-甲基-D-天冬氨酸受体（NMDAR）是谷氨酸门控钙通道，以其人工激动剂命名。NMDAR 参与正常和病理生理条件下的细胞增殖。然而，在单个细胞中，NMDAR 在有丝分裂期间的作用尚未被探索。我们发现，皮质星形胶质细胞中内源性 NMDAR 诱发的神经递质诱导的钙内流在有丝分裂期间是短暂的。在转染了 NMDAR 的 NR1/NR2A 亚基的 HEK293 细胞中也发生了同样的情况。这种短暂的钙内流是由于细胞周期蛋白 B/CDK1 对 NMDAR 的第一细胞内环（NR1 的 S584 和 NR2A 的 S580）的磷酸化。表达磷酸模拟突变体导致钙内流短暂增加，并增强了 NMDAR 的失活，而与细胞周期阶段无关。磷酸模拟突变体增加了有丝分裂间期的钙进入，并在有丝分裂期间产生了几种变化：有丝分裂指数增加、滞后染色体的细胞数量增加和中心粒周围物质的碎片化。总之，通过控制细胞溶质钙，NMDAR 调节有丝分裂和可能的细胞分化/增殖。我们的结果表明，细胞周期蛋白 B/CDK1 在有丝分裂期间对 NMDAR 的磷酸化对于保持有丝分裂保真度是必需的。改变细胞周期蛋白 B/CDK1 对 NMDAR 的调节可能导致非整倍体和癌症。
