Dopamine D2 receptor activation leads to an up-regulation of glial cell line-derived neurotrophic factor via Gβγ-Erk1/2-dependent induction of Zif268.
Dopamine D2 receptor activation leads to an up-regulation of glial cell line-derived neurotrophic factor via Gβγ-Erk1/2-dependent induction of Zif268.
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DOI：
10.1111/jnc.12178
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发表时间：
2013-04
影响因子：
4.7
通讯作者：
Ron D
中科院分区：
文献类型：
--
作者：
Ahmadiantehrani S;Ron D
胶质细胞源性神经营养因子（GDNF）是一种对多巴胺能神经元的发育、存活和功能至关重要的强效生长因子。GDNF表达的分子机制仍然是难以捉摸的，因此，我们着手确定一个信号通路，支配GDNF水平。我们发现，用多巴胺D2受体（D2 R）激动剂quinpirole处理分化的多巴胺能样SH-SY 5 Y细胞和大鼠中脑切片，触发了GDNF表达的增加，这在时间上是由Zif 268（一种由立即早期基因编码的DNA结合转录因子）水平的增加引起的。此外，D2 R抑制剂雷氯必利阻断了钾诱导的SH-SY 5 Y细胞多巴胺释放后GDNF和Zif 268表达的增加。我们使用腺病毒递送靶向Zif 268的小发夹RNA（shRNA）来下调其表达，并发现Zif 268是D2 R介导的GDNF上调所特别需要的。此外，D2 R介导的GDNF和Zif 268表达的诱导依赖于Gβγ介导的信号传导和细胞外信号调节激酶1/2（Erk 1/2）的激活。重要的是，使用染色质免疫沉淀（ChIP）测定，我们鉴定了Zif 268与GDNF启动子的直接关联。这些结果表明，D2 R激活诱导Zif 268水平的Gβγ和Erk 1/2依赖性增加，其功能是直接上调GDNF的表达。
Glial cell line-derived neurotrophic factor (GDNF) is a potent growth factor essential to the development, survival, and function of dopaminergic neurons. The molecular mechanisms underlying GDNF expression remain elusive, thus, we set out to identify a signaling pathway that governs GDNF levels. We found that treatment of both differentiated dopaminergic-like SH-SY5Y cells and rat midbrain slices with the dopamine D2 receptor (D2R) agonist, quinpirole, triggered an increase in the expression of GDNF that was temporally preceded by an increase in the levels of Zif268, a DNA-binding transcription factor encoded by an immediate-early gene. Moreover, the D2R inhibitor raclopride blocked the increase of both GDNF and Zif268 expression following potassium-evoked dopamine release in SH-SY5Y cells. We used adenoviral delivery of small hairpin RNA (shRNA) targeting Zif268 to downregulate its expression and found that Zif268 is specifically required for the D2R-mediated upregulation of GDNF. Furthermore, the D2R-mediated induction of GDNF and Zif268 expression was dependent on Gβγ-mediated signaling and activation of extracellular signal-regulated kinase 1/2 (Erk1/2). Importantly, using chromatin immunoprecipitation (ChIP) assay, we identified a direct association of Zif268 with the GDNF promoter. These results suggest that D2R activation induces a Gβγ- and Erk1/2-dependent increase in the level of Zif268, which functions to directly upregulate the expression of GDNF.
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影响因子：
10.6
作者：
Carnicella, Sebastien;Ahmadiantehrani, Somayeh;He, Dao-Yao;Nielsen, Carsten K.;Bartlett, Selena E.;Janak, Patricia H.;Ron, Dorit
通讯作者：
Ron, Dorit
DOI：
10.1006/bbrc.1999.0286
发表时间：
1999-03-05
影响因子：
3.1
作者：
Choi, EY;Jeong, DW;Baik, JH
通讯作者：
Baik, JH
影响因子：
2.3
作者：
Camicella, Sebastien;Amamoto, Ryoji;Ron, Dorit
通讯作者：
Ron, Dorit
影响因子：
5.3
作者：
Ghahremani, MH;Forget, C;Albert, PR
通讯作者：
Albert, PR
影响因子：
5.3
作者：
Golden, JP;DeMaro, JA;Johnson, EM
通讯作者：
Johnson, EM