Division of Cell Biology I, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
PLoS One. 2019 Jan 7;14(1):e0209563. doi: 10.1371/journal.pone.0209563. eCollection 2019.
The nonspecific divalent cation channel TRPM7 (transient receptor potential-melastatin-like 7) is involved in many Ca2+ and Mg2+-dependent cellular processes, including survival, proliferation and migration. TRPM7 expression predicts metastasis and recurrence in breast cancer and several other cancers. In cultured cells, it can induce an invasive phenotype by promoting Ca2+-mediated epithelial-mesenchymal transition. We previously showed that in neuroblastoma cells that overexpress TRPM7 moderately, stimulation with Ca2+-mobilizing agonists leads to a characteristic sustained influx of Ca2+. Here we report that sustained influx through TRPM7 is abruptly abrogated by elevating intracellular levels of cyclic adenosine monophosphate (cAMP). Using pharmacological inhibitors and overexpression studies we show that this blockage is mediated by the cAMP effector Protein Kinase A (PKA). Mutational analysis demonstrates that the Serine residue S1269, which is present proximal to the coiled-coil domain within the protein c-terminus, is responsible for sensitivity to cAMP.
非特异性二价阳离子通道 TRPM7（瞬时受体电位 - 梅拉斯坦样 7）参与许多 Ca2+和 Mg2+依赖的细胞过程，包括存活、增殖和迁移。TRPM7 的表达可预测乳腺癌和其他几种癌症的转移和复发。在培养的细胞中，它可以通过促进 Ca2+介导的上皮 - 间充质转化来诱导侵袭表型。我们之前表明，在过度表达 TRPM7 的神经母细胞瘤细胞中，用动员 Ca2+的激动剂刺激会导致特征性的持续 Ca2+内流。在这里，我们报告说，通过升高细胞内环腺苷单磷酸（cAMP）水平，可突然阻断通过 TRPM7 的持续内流。我们使用药理学抑制剂和过表达研究表明，这种阻断是由 cAMP 效应物蛋白激酶 A（PKA）介导的。突变分析表明，存在于蛋白 C 末端卷曲螺旋结构域附近的丝氨酸残基 S1269 对 cAMP 敏感。
