TGF‐β1 enhances Kv2.1 potassium channel protein expression and promotes maturation of cerebellar granule neurons
TGF‐β1 enhances Kv2.1 potassium channel protein expression and promotes maturation of cerebellar granule neurons
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DOI：
10.1002/jcp.22735
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发表时间：
2012-01
影响因子：
5.6
通讯作者：
Jia-Li Zhuang;Chang-Ying Wang;Meng‐Hua Zhou;Kai-Zheng Duan;Y. Mei
中科院分区：
文献类型：
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作者：
Jia-Li Zhuang;Chang-Ying Wang;Meng‐Hua Zhou;Kai-Zheng Duan;Y. Mei
细胞因子转化生长因子-β（TGF-β）家族成员参与多种生理过程。虽然已知TGF-β在哺乳动物中枢神经系统（CNS）中发挥多种作用，但尚未探索其在神经元发育中的作用。我们研究了TGF-β1对大鼠原代小脑颗粒神经元（CGNs）电生理特性和成熟的影响。我们报告称，与TGF-β1孵育以剂量和时间依赖性方式增加延迟整流钾电流（IK）幅度，但不影响通道的动力学特性。暴露于TGF-β1（20 ng/ml）36 h导致IK振幅增加37.2%。关键Kv2.1通道蛋白的mRNA水平没有显著变化，但翻译阻断消除了蛋白水平和通道活性的增加，认为TGF-β1通过上调Kv2.1通道蛋白的翻译来增加IK振幅。虽然TGF-β1处理不影响蛋白激酶A（PKA）的活性，并且用毛喉素组成性激活PKA未能增加IK振幅，但抑制PKA阻止了通道上调，表明基础PKA活性是TGF-β1刺激IK通道活性所必需的。TGF-β1还促进了γ-氨基丁酸（GABAA）受体α6亚基（成熟CGN的标志物）的表达，TGF-β1减少了去极化刺激期间的钙内流。TGF-β1的作用仅在狭窄的发育时间窗内观察到，并且随着CGN成熟而消失。这些结果表明，TGF-β1上调K+通道表达和IK电流，从而促进CGN成熟。J.细胞。227：297-307，2012。© 2011 Wiley Periodicals，Inc.
Members of the transforming growth factor‐β (TGF‐β) family of cytokines are involved in diverse physiological processes. Although TGF‐β is known to play multiple roles in the mammalian central nervous system (CNS), its role in neuronal development has not been explored. We have studied the effects of TGF‐β1 on the electrophysiological properties and maturation of rat primary cerebellar granule neurons (CGNs). We report that incubation with TGF‐β1 increased delayed rectifier potassium current (IK) amplitudes in a dose‐ and time‐dependent manner, but did not affect the kinetic properties of the channel. Exposure to TGF‐β1 (20 ng/ml) for 36 h led to a 37.2% increase in IK amplitudes. There was no significant change in mRNA levels for the key Kv2.1 channel protein, but translation blockade abolished the increase in protein levels and channel activity, arguing that TGF‐β1 increases IK amplitudes by upregulating translation of the Kv2.1 channel protein. Although TGF‐β1 treatment did not affect the activity of protein kinase A (PKA), and constitutive activation of PKA with forskolin failed to increase IK amplitudes, inhibition of PKA prevented channel upregulation, demonstrating that basal PKA activity is required for TGF‐β1 stimulation of IK channel activity. TGF‐β1 also promoted the expression of the γ‐aminobutyric acid (GABAA) receptor α6 subunit, a marker of mature CGNs, and calcium influx during depolarizing stimuli was reduced by TGF‐β1. The effects of TGF‐β1 were only observed during a narrow developmental time‐window, and were lost as CGNs matured. These findings suggest that TGF‐β1 upregulates K+ channel expression and IK currents and thereby promotes CGN maturation. J. Cell. Physiol. 227: 297–307, 2012. © 2011 Wiley Periodicals, Inc.