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-SY 5Y neuroblastoma (NB) cells treated with all-trans-retinoic acid (RA) in th e absence or presence of the neurotrophin brain-derived neurotrophic factor (BDNF). Both treatments produced a strong increase in the percentage of ce lls differentiated along the neuronal pathway, with an orientation to a cho linergic phenotype, while a minority of cells displayed a glial phenotype p articularly evident after long-term exposure to the inducers. Differentiati on of NB cells was accompanied by an increase in herg gene transcription, w hich attained its maximum after 6 days of treatment with RA and was not fur ther increased by BDNF. This effect evidently reflected on HERG currents: I n fact, RA produced an increase in HERG current density which was strongly potentiated by BDNF. Moreover, RA treatment affected the biophysical proper ties of I-HERG inducing an increase in the deactivation time constant and a left shift of the activation curve. These effects were not substantially a ffected by BDNF. This modulation of I-HERG influenced the value of the rest ing potential (V-REST), which resulted significantly hyperpolarized in (RA with or without BDNF)-treated cells. Interestingly, these effects were abse nt in the glial population, which prevailed in cultures after long-term exp osure to the inducers. On the whole, we demonstrate that besides expressing IRK currents, NB cells display another strategy to hyperpolarize their V-R EST, based on the appropriate modulation of HERG currents. Different from w hat happens in normal neuroblast development, the latter are never lost by cancer cells despite the progression of these cells along the neuronal diff erentiative pathway, raising intriguing questions about the role of HERG cu rrents in tumour behavior. (C) 1999 John Wiley & Sons, Inc.