Centro de Investigaciones Biomédicas en Red Enfermedades Neurodegenerativas (CIBERNED) and Departamento de Neurociencias, Universidad del País Vasco, Leioa, Spain.
Cell Calcium. 2011 Nov;50(5):468-72. doi: 10.1016/j.ceca.2011.08.002. Epub 2011 Sep 8.
We have previously shown that P2X7 receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates chronic experimental autoimmune encephalomyelitis. Here, we have explored the putative association of functionally relevant single nucleotide polymorphisms of the P2X7 receptor gene with multiple sclerosis. We found that T allele of rs17525809 polymorphism, which yields an Ala-76 to Val change in the extracellular domain, is more frequent in multiple sclerosis patients than in controls. Importantly, P2X7 variants with Val show a gain-of-function consisting in higher calcium permeability, larger electrophysiological responses and higher ethidium uptake, and enhance the effect of the also gain-of-function His-155 to Tyr substitution (rs208294) in the haplotype formed by these two variants. These findings may contribute to define the genetic background predisposing for multiple sclerosis and its pathophysiology.
我们之前已经表明，P2X7 受体阻断可防止少突胶质细胞中的 ATP 兴奋性毒性，并改善慢性实验性自身免疫性脑脊髓炎。在这里，我们探讨了 P2X7 受体基因的功能相关单核苷酸多态性与多发性硬化症之间的潜在关联。我们发现，rs17525809 多态性的 T 等位基因，在外源域产生 Ala-76 到 Val 的变化，在多发性硬化症患者中比对照组更为常见。重要的是，具有 Val 的 P2X7 变体具有功能获得性，表现为更高的钙通透性、更大的电生理反应和更高的 ethidium 摄取，并增强了由这两个变体形成的单倍型中同样具有功能获得性的 His-155 到 Tyr 取代（rs208294）的作用。这些发现可能有助于确定多发性硬化症及其病理生理学的遗传背景易感性。
