Modulation of HERG current and herg gene expression during retinoic acid treatment of human neuroblastoma cells: potentiating effects of BDNF.
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.
Department of Experimental Pathology and Oncology, University of Firenze, Viale G. B. Morgagni, 50, 50134 Firenze, Italy.
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A
Arcangeli
B
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Rosati
O
O
Crociani
A
A
Cherubini
L
L
Fontana
B
B
Passani
E
E
Wanke
M
M
Olivotto
D000109:Acetylcholine / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D027682:Cation Transport Proteins; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins; D004357:Drug Synergism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009447:Neuroblastoma / Q000473:pathology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D009363:Neoplasm Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014212:Tretinoin; D000109:Acetylcholine; D011188:Potassium