Activation of phosphatidylinositol-linked D1-like receptor modulates FGF-2 expression in astrocytes via IP3-dependent Ca2+ signaling.
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 D(1) or D(2) elicits FGF-2 biosynthesis and secretion in astrocytes. Here, we report that astrocytic FGF-2 expression is also regulated by phosphatidylinositol (PI)-linked D(1)-like receptor. SKF83959, a selective PI-linked D(1)-like receptor agonist, upregulates the levels of FGF-2 protein in striatal astrocyte cultures in classical dopamine D(1) and D(2) 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/Ca(2+)/calmodulin-dependent protein kinase is an uncharted intracellular signaling pathway that is crucial for the regulation of FGF-2 synthesis in astrocytes. PI-linked D(1)-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.
Zhang
Xinhua
X
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Zhou
Zheng
Z
Wang
Dakui
D
Li
Aiqun
A
Yin
Yanqing
Y
Gu
Xiaosong
X
Ding
Fei
F
Zhen
Xuechu
X
Zhou
Jiawei
J
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D001552:Benzazepines / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001552:Benzazepines; D017077:Culture Media, Conditioned; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D010716:Phosphatidylinositols; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D016222:Fibroblast Growth Factor 2; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C080703:SK&F 83959; D015544:Inositol 1,4,5-Trisphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase