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

Abstract

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.