GDF-15 enhances intracellular Ca2+ by increasing Cav1.3 expression in rat cerebellar granule neurons.
GDF-15 enhances intracellular Ca2+ by increasing Cav1.3 expression in rat cerebellar granule neurons.
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GDF-15 通过增加大鼠中 Cav1.3 的表达来增强细胞内 Ca2
DOI：
10.1042/bcj20160362
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发表时间：
2016-07-01
期刊：
影响因子：
--
通讯作者：
Mei YA
中科院分区：
文献类型：
--
作者：
Lu JM;Wang CY;Hu C;Fang YJ;Mei YA
GDF-15（生长/分化因子15）是TGF（转化生长因子）-β超家族的新成员，在中枢和周围神经系统中起重要作用。我们之前报道过，GDF-15通过TβRII （TGF-β受体II）增加延迟的向外K+电流和Kv2.1 α亚基表达，激活大鼠CGNs（小脑颗粒神经元）中的Src激酶和Akt/mTOR（哺乳动物雷帕霉素靶点）信号传导。在本研究中，我们发现用GDF-15处理CGNs 24小时增加细胞内Ca2+浓度（[Ca2+]i），响应于膜去极化，由Ca2+成像确定。全细胞电流记录表明，GDF-15增加了内向Ca2+电流（ICa），而不改变Ca2+通道的稳态激活。硝苯地平（l型Ca2+通道抑制剂）治疗可消除gdf -15诱导的[Ca2+]i和ICa的增加。gdf -15诱导的ICa升高是通过上调Cav1.3 α亚基介导的，通过抑制Akt/mTOR和ERK（细胞外信号调节激酶）途径以及药理抑制src介导的TβRII磷酸化来减弱ICa。鉴于Cav1.3不仅是Ca2+内流的通道，也是一种转录调节剂，我们的数据证实了GDF-15通过TβRII和非smad通路的激活诱导蛋白表达，并为GDF-15在神经元中的功能机制提供了新的见解。
GDF-15 (growth/differentiation factor 15) is a novel member of the TGF (transforming growth factor)-β superfamily that has critical roles in the central and peripheral nervous systems. We reported previously that GDF-15 increased delayed rectifier outward K+ currents and Kv2.1 α subunit expression through TβRII (TGF-β receptor II) to activate Src kinase and Akt/mTOR (mammalian target of rapamycin) signalling in rat CGNs (cerebellar granule neurons). In the present study, we found that treatment of CGNs with GDF-15 for 24 h increased the intracellular Ca2+ concentration ([Ca2+]i) in response to membrane depolarization, as determined by Ca2+ imaging. Whole-cell current recordings indicated that GDF-15 increased the inward Ca2+ current (ICa) without altering steady-state activation of Ca2+ channels. Treatment with nifedipine, an inhibitor of L-type Ca2+ channels, abrogated GDF-15-induced increases in [Ca2+]i and ICa. The GDF-15-induced increase in ICa was mediated via up-regulation of the Cav1.3 α subunit, which was attenuated by inhibiting Akt/mTOR and ERK (extracellular-signal-regulated kinase) pathways and by pharmacological inhibition of Src-mediated TβRII phosphorylation. Given that Cav1.3 is not only a channel for Ca2+ influx, but also a transcriptional regulator, our data confirm that GDF-15 induces protein expression via TβRII and activation of a non-Smad pathway, and provide novel insight into the mechanism of GDF-15 function in neurons.
影响因子：
2.2
作者：
Liu F;Wu B;Du Y;Wu Y;Chen H;Xia F;Jin Z;Xu X
通讯作者：
Xu X