Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation
Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation
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DOI：
10.1523/jneurosci.2180-07.2007
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发表时间：
2007-07-25
影响因子：
5.3
通讯作者：
Ozawa, Seiji
中科院分区：
文献类型：
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作者：
Ishiuchi, Shogo;Yoshida, Yukari;Ozawa, Seiji
已经积累的证据表明，胶质母细胞瘤细胞释放和利用谷氨酸增殖和迁移的自分泌或旁分泌环通过钙渗透AMPA型谷氨酸受体。在这里，我们表明，AMPA受体介导的Ca 2+信号调节胶质母细胞瘤细胞的生长和运动通过激活Akt。通过Ca 2+渗透性AMPA受体提供的Ca 2+磷酸化Akt的Ser-473，从而促进增殖和迁移。Akt的显性负性形式抑制细胞增殖和迁移加速过表达的Ca 2+渗透AMPA受体。与此相反，Akt的组成型活性形式的引入拯救了肿瘤细胞免于通过递送G1 uR 2 cDNA将Ca 2+可渗透的AMPA受体转化为Ca 2+不可渗透的受体而诱导的凋亡。因此，Akt在胶质母细胞瘤细胞中作为AMPA受体介导的Ca 2+信号传导的下游效应物发挥作用。谷氨酸-AMPA受体-Akt通路的激活可能有助于人类胶质母细胞瘤的高度间变性和侵袭性生长。这种新的途径可能会提供一个替代的治疗靶点。
Evidence has been accumulated that glioblastoma cells release and exploit glutamate for proliferation and migration by autocrine or paracrine loops through Ca2+-permeable AMPA-type glutamate receptors. Here, we show that Ca2+ signaling mediated by AMPA receptor regulates the growth and motility of glioblastoma cells via activation of Akt. Ca2+ supplied through Ca2+-permeable AMPA receptor phosphorylated Akt at Ser-473, thereby facilitating proliferation and mobility. A dominant-negative form of Akt inhibited cell proliferation and migration accelerated by overexpression of Ca2+-permeable AMPA receptor. In contrast, introduction of a constitutively active form of Akt rescued tumor cells from apoptosis induced by the conversion of Ca2+-permeable AMPA receptor to Ca2+-impermeable receptors by the delivery of G1uR2 cDNA. Therefore, Akt functions as downstream effectors for Ca2+-signaling mediated by AMPA receptor in glioblastoma cells. The activation of the glutamate-AMPA receptor-Akt pathway may contribute to the high degree of anaplasia and invasive growth of human glioblastoma. This novel pathway might give an alternative therapeutic target.