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 andHERG currents (IHERG) was studied in SH-SY5Y neu-roblastoma (NB) cells treated with all-trans-retinoic acid(RA) in the absence or presence of the neurotrophinbrain-derived neurotrophic factor (BDNF). Both treat-ments produced a strong increase in the percentage ofcells differentiated along the neuronal pathway, with anorientation to a cholinergic phenotype, while a minorityof cells displayed a glial phenotype particularly evidentafter long-term exposure to the inducers. Differentiationof NB cells was accompanied by an increase in herg genetranscription, which attained its maximum after 6 daysof treatment with RA and was not further increased byBDNF. This effect evidently reflected on HERG cur-rents: In fact, RA produced an increase in HERG cur-rent density which was strongly potentiated by BDNF.Moreover, RA treatment affected the biophysical prop-erties of IHERG, inducing an increase in the deactivationtime constant and a left shift of the activation curve.These effects were not substantially affected by BDNF.This modulation of IHERGinfluenced the value of theresting potential (VREST), which resulted significantlyhyperpolarized in (RA with or without BDNF)-treatedcells. Interestingly, these effects were absent in the glialpopulation, which prevailed in cultures after long-termexposure to the inducers. On the whole, we demonstratethat besides expressing IRK currents, NB cells displayanother strategy to hyperpolarize their VREST, based onthe appropriate modulation of HERG currents. Differ-ent from what happens in normal neuroblast develop-ment, the latter are never lost by cancer cells despite theprogression of these cells along the neuronal differentia-tive pathway, raising intriguing questions about the roleof HERG currents in tumour behavior