Brandalise Federico, Ratto Daniela, Leone Roberta, Olivero Federico, Roda Elisa, Locatelli Carlo Alessandro, Grazia Bottone Maria, Rossi Paola
Department of Fundamental Neurosciences (NEUFO), University of Geneva, Geneva, Switzerland.
Department of Biology and Biotechnology "L. Spallanzani," University of Pavia, Pavia, Italy.
Front Neurosci. 2020 Nov 30;14:595664. doi: 10.3389/fnins.2020.595664. eCollection 2020.
In the last decades, increasing evidence has revealed that a large number of channel protein and ion pumps exhibit impaired expression in cancers. This dysregulation is responsible for high proliferative rates as well as migration and invasiveness, reflected in the recently coined term oncochannelopathies. In glioblastoma (GBM), the most invasive and aggressive primary brain tumor, GBM cells modify their ionic equilibrium in order to change their volume as a necessary step prior to migration. This mechanism involves increased expression of BK channels and downregulation of the normally widespread Kir4.1 channels, as noted in GBM biopsies from patients. Despite a large body of work implicating BK channels in migration in response to an artificial intracellular calcium rise, little is known about how this channel acts in GBM cells at resting membrane potential (RMP), as compared to other channels that are constitutively open, such as Kir4.1. In this review we propose that a residual fraction of functionally active Kir4.1 channels mediates a small, but continuous, efflux of potassium at the more depolarized RMP of GBM cells. In addition, coinciding with transient membrane deformation and the intracellular rise in calcium concentration, brief activity of BK channels can induce massive and rapid cytosolic water loss that reduces cell volume (cell shrinkage), a necessary step for migration within the brain parenchyma.
在过去几十年中，越来越多的证据表明，大量通道蛋白和离子泵在癌症中表达受损。这种失调导致了高增殖率以及迁移和侵袭性，这在最近新造的术语“肿瘤通道病”中得到了体现。在胶质母细胞瘤（GBM）中，这是最具侵袭性和攻击性的原发性脑肿瘤，GBM细胞会改变其离子平衡以改变其体积，这是迁移之前的必要步骤。如在患者的GBM活检中所观察到的，这种机制涉及BK通道表达增加以及通常广泛分布的Kir4.1通道下调。尽管有大量工作表明BK通道在人工诱导细胞内钙升高时参与迁移，但与其他组成性开放的通道（如Kir4.1）相比，关于该通道在GBM细胞静息膜电位（RMP）下如何发挥作用却知之甚少。在本综述中，我们提出，功能活跃的Kir4.1通道的残余部分在GBM细胞更去极化的RMP下介导少量但持续的钾外流。此外，与短暂的膜变形和细胞内钙浓度升高同时发生的是，BK通道的短暂活动可诱导大量且快速的胞质失水，从而减小细胞体积（细胞收缩），这是在脑实质内迁移的必要步骤。
