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The Journal of Neuroscience, June 17, 2009, 29(24):7766-7775; doi:10.1523/JNEUROSCI.0389-09.2009

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Neurobiology of Disease
Activation of Phosphatidylinositol-Linked D₁-Like Receptor Modulates FGF-2 Expression in Astrocytes via IP3-Dependent Ca²⁺ Signaling

Xinhua Zhang,^1,2,4 Zheng Zhou,² Dakui Wang,^2,3 Aiqun Li,¹ Yanqing Yin,² Xiaosong Gu,³ Fei Ding,³ Xuechu Zhen,⁵ and Jiawei Zhou²

¹Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, ²Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, ³Jiangsu Key Laboratory of Neuroregeneration and ⁴Department of Anatomy, Nantong University School of Medicine, Nantong, Jiangsu 226001, China, and ⁵State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China

Correspondence should be addressed to either of the following: Dr. Jiawei Zhou, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China, Email: jwzhou{at}ion.ac.cn; or Dr. Xuechu Zhen, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China, Email: xczhen{at}mail.shcnc.ac.cn

Fibroblast growth factor-2 (FGF-2) is predominantly synthesized and secreted by astrocytes in adult brain. Our previous study showed that activation of classical dopamine receptor D₁ or D₂ elicits FGF-2 biosynthesis and secretion in astrocytes. Here, we report that astrocytic FGF-2 expression is also regulated by phosphatidylinositol (PI)-linked D₁-like receptor. SKF83959, a selective PI-linked D₁-like receptor agonist, upregulates the levels of FGF-2 protein in striatal astrocyte cultures in classical dopamine D₁ and D₂ receptor-independent manner. The conditional medium derived from SKF83959-activated astrocytes promoted the number of TH⁺ neurons in vitro. Treatment of astrocytes with SKF83959 increased intracellular calcium in two phases. Inhibition of intracellular calcium oscillation by inositol 1,4,5-triphosphate (IP3) inhibitors blocked the SKF83959-induced increase in FGF-2 expression. Moreover, intraperitoneal administration of SKF83959 reversed l-methyl-4-phenyl-l,2,3,6-tetrahydropypridine (MPTP)-induced reduction in FGF-2 expression in both the striatum and ventral midbrain and resulted in marked protection of dopaminergic neurons from MPTP-induced neurotoxicity. These results indicate that IP3/Ca²⁺/calmodulin-dependent protein kinase is an uncharted intracellular signaling pathway that is crucial for the regulation of FGF-2 synthesis in astrocytes. PI-linked D₁-like receptor plays an important role in the regulation of astrocytic FGF-2 expression and neuroprotection which may provide a potential target for the drug discovery in Parkinson's disease.

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Received Jan. 24, 2009; revised May 5, 2009; accepted May 5, 2009.

Correspondence should be addressed to either of the following: Dr. Jiawei Zhou, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China, Email: jwzhou{at}ion.ac.cn; or Dr. Xuechu Zhen, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China, Email: xczhen{at}mail.shcnc.ac.cn

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