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The Journal of Neuroscience, July 25, 2007, 27(30):7987-8001; doi:10.1523/JNEUROSCI.2180-07.2007

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Neurobiology of Disease
Ca²⁺-Permeable AMPA Receptors Regulate Growth of Human Glioblastoma via Akt Activation

Shogo Ishiuchi,¹ Yukari Yoshida,² Kenichi Sugawara,¹ Masanori Aihara,¹ Toshiyuki Ohtani,¹ Takashi Watanabe,¹ Nobuhito Saito,¹ Keisuke Tsuzuki,² Haruo Okado,⁴ Akiko Miwa,⁴ Yoichi Nakazato,³ and Seiji Ozawa²

¹Departments of Neurosurgery, ²Neurophysiology, and ³Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan, and ⁴Department of Molecular Physiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu 183-8526, Japan

Correspondence should be addressed to Dr. Shogo Ishiuchi, Department of Neurosurgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Email: ishogo{at}showa.gunma-u.ac.jp

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 GluR2 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.

Key words: brain tumor; glioblastoma; AMPA receptors; Akt; invasion; calcium signaling

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Received Dec. 13, 2006; revised May 11, 2007; accepted June 6, 2007.

Correspondence should be addressed to Dr. Shogo Ishiuchi, Department of Neurosurgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Email: ishogo{at}showa.gunma-u.ac.jp

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