Mönkkönen Kati S, Hakumäki Juhana M, Hirst Robert A, Miettinen Riitta A, O'Callaghan Christopher, Männistö Pekka T, Laitinen Jarmo T
Department of Pharmacology & Toxicology, University of Kuopio, Kuopio, Finland.
BMC Neurosci. 2007 Apr 12;8:26. doi: 10.1186/1471-2202-8-26.
In the CNS, the heterotrimeric G protein Galphai2 is a minor Galpha subunit with restricted localization in the ventricular regions including the ependymal cilia. The localization of Galphai2 is conserved in cilia of different tissues, suggesting a particular role in ciliary function. Although studies with Galphai2-knockout mice have provided information on the role of this Galpha subunit in peripheral tissues, its role in the CNS is largely unknown. We used intracerebroventricular (icv) antisense administration to clarify the physiological role of Galphai2 in the ventricular system.
High resolution MRI studies revealed that continuous icv-infusion of Galphai2-specific antisense oligonucleotide caused unilateral ventricular dilatation that was restricted to the antisense-receiving ventricle. Microscopic analysis demonstrated ependymal cell damage and loss of ependymal cilia. Attenuation of Galphai2 in ependymal cells was confirmed by immunohistochemistry. Ciliary beat frequency measurements on cultured ependymal cells indicated that antisense administration resulted in ciliary stasis.
Our results establish that Galphai2 has an essential regulatory role in ciliary function and CSF homeostasis.
在中枢神经系统（CNS）中，异源三聚体G蛋白Gαi2是一种次要的Gα亚基，在包括室管膜纤毛在内的脑室区域定位受限。Gαi2的定位在不同组织的纤毛中是保守的，这表明其在纤毛功能中具有特定作用。尽管对Gαi2基因敲除小鼠的研究提供了关于该Gα亚基在周围组织中作用的信息，但其在中枢神经系统中的作用仍 largely未知。我们采用脑室内（icv）反义给药来阐明Gαi2在脑室系统中的生理作用。
高分辨率MRI研究显示，持续脑室内输注Gαi2特异性反义寡核苷酸会导致单侧脑室扩张，且仅限于接受反义药物的脑室。显微镜分析表明室管膜细胞损伤和室管膜纤毛丧失。免疫组织化学证实室管膜细胞中Gαi2减少。对培养的室管膜细胞进行纤毛摆动频率测量表明，反义给药导致纤毛停滞。
我们的结果表明，Gαi2在纤毛功能和脑脊液稳态中具有重要的调节作用。
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