Retinoic Acid-Differentiated Neuroblastoma SH-SY5Y Is an Accessible In Vitro Model to Study Native Human Acid-Sensing Ion Channels 1a (ASIC1a)

SIMPLE SUMMARY: Human neuroblastoma SH-SY5Y is used in neurobiology for studying various neuropathophysiological processes. In this study, we differentiated neuroblastoma cells into a neuronal-like phenotype with retinoic acid and studied if functional acid-sensing, transient receptor potential vanilloid-1 and ankyrin-1 ion channels were expressed in it. We found that homomeric acid-sensing ion channels 1a were expressed predominantly and yielded large ionic currents that can be modulated with different ligands. This channel plays important roles in synaptic plasticity, neurodegeneration, and pain perception. Thus, retinoic acid-treated neuroblastoma is a suitable model system for pharmacological testing on native human acid-sensing ion channels 1a. This approach can facilitate the development of new drugs for neuroprotection and pain management. ABSTRACT: Human neuroblastoma SH-SY5Y is a prominent neurobiological tool used for studying neuropathophysiological processes. We investigated acid-sensing (ASIC) and transient receptor potential vanilloid-1 (TRPV1) and ankyrin-1 (TRPA1) ion channels present in untreated and differentiated neuroblastoma SH-SY5Y to propose a new means for their study in neuronal-like cells. Using a quantitative real-time PCR and a whole-cell patch-clamp technique, ion channel expression profiles, functionality, and the pharmacological actions of their ligands were characterized. A low-level expression of ASIC1a and ASIC2 was detected in untreated cells. The treatment with 10 μM of retinoic acid (RA) for 6 days resulted in neuronal differentiation that was accompanied by a remarkable increase in ASIC1a expression, while ASIC2 expression remained almost unaltered. In response to acid stimuli, differentiated cells showed prominent ASIC-like currents. Detailed kinetic and pharmacological characterization suggests that homomeric ASIC1a is a dominant isoform among the present ASIC channels. RA-treatment also reduced the expression of TRPV1 and TRPA1, and minor electrophysiological responses to their agonists were found in untreated cells. Neuroblastoma SH-SY5Y treated with RA can serve as a model system to study the effects of different ligands on native human ASIC1a in neuronal-like cells. This approach can improve the characterization of modulators for the development of new neuroprotective and analgesic drugs.