Arcangeli A, Rosati B, Crociani O, Cherubini A, Fontana L, Passani B, Wanke E, Olivotto M
Department of Experimental Pathology and Oncology, University of Firenze, Viale G. B. Morgagni, 50, 50134 Firenze, Italy.
J Neurobiol. 1999 Aug;40(2):214-25.
The modulation of herg gene and HERG currents (I(HERG)) was studied in SH-SY5Y neuroblastoma (NB) cells treated with all-trans-retinoic acid (RA) in the absence or presence of the neurotrophin brain-derived neurotrophic factor (BDNF). Both treatments produced a strong increase in the percentage of cells differentiated along the neuronal pathway, with an orientation to a cholinergic phenotype, while a minority of cells displayed a glial phenotype particularly evident after long-term exposure to the inducers. Differentiation of NB cells was accompanied by an increase in herg gene transcription, which attained its maximum after 6 days of treatment with RA and was not further increased by BDNF. This effect evidently reflected on HERG currents: In fact, RA produced an increase in HERG current density which was strongly potentiated by BDNF. Moreover, RA treatment affected the biophysical properties of I(HERG), inducing an increase in the deactivation time constant and a left shift of the activation curve. These effects were not substantially affected by BDNF. This modulation of I(HERG) influenced the value of the resting potential (V(REST)), which resulted significantly hyperpolarized in (RA with or without BDNF)-treated cells. Interestingly, these effects were absent in the glial population, which prevailed in cultures after long-term exposure to the inducers. On the whole, we demonstrate that besides expressing IRK currents, NB cells display another strategy to hyperpolarize their V(REST), based on the appropriate modulation of HERG currents. Different from what happens in normal neuroblast development, the latter are never lost by cancer cells despite the progression of these cells along the neuronal differentiative pathway, raising intriguing questions about the role of HERG currents in tumour behavior.
在有无神经营养因子脑源性神经营养因子（BDNF）存在的情况下，研究了全反式维甲酸（RA）处理的SH-SY5Y神经母细胞瘤（NB）细胞中herg基因和HERG电流（I(HERG)）的调节情况。两种处理均使沿神经元途径分化的细胞百分比大幅增加，并趋向于胆碱能表型，而少数细胞表现出胶质细胞表型，在长期暴露于诱导剂后尤为明显。NB细胞的分化伴随着herg基因转录的增加，在用RA处理6天后达到最大值，且BDNF不会使其进一步增加。这种效应显然反映在HERG电流上：事实上，RA使HERG电流密度增加，而BDNF则强烈增强了这种增加。此外，RA处理影响了I(HERG)的生物物理特性，导致失活时间常数增加和激活曲线左移。这些效应基本上不受BDNF的影响。I(HERG)的这种调节影响了静息电位（V(REST)）的值，在用（含或不含BDNF的）RA处理的细胞中，静息电位显著超极化。有趣的是，在长期暴露于诱导剂后占主导地位的胶质细胞群体中，这些效应并不存在。总体而言，我们证明除了表达IRK电流外，NB细胞还展示了另一种使V(REST)超极化的策略，即基于对HERG电流的适当调节。与正常神经母细胞发育不同的是，尽管癌细胞沿着神经元分化途径进展，但后者从未丢失，这引发了关于HERG电流在肿瘤行为中作用的有趣问题。
