From the adrenergic SH-SY5Y human neuroblastoma clone, we isolated a subclone (21S) endowed with a glial-oriented phenotype. At difference from the parental clone, 21S cells responded to depolarizing stimuli with overshooting action potentials, whose repolarization phase was composed of an initial rapid episode, followed by a long-lasting plateau and a slow return to the resting potential (V-REST). The action potential depolarization phase was sustained by a TTX-sensitive Na+ current, while the first repolarizing episode was produced by the scanty delayed rectifier potassium current (I-KDR) expressed in 21S cells. The bulk of repolarization, including the after-hyperpolarization, was sustained by the human eag related (HERG) potassium current (I-HERG)) that also governs V-REST in 21S cells. This double role of I-HERG, together with the poor expression of I-KDRs, represents a novel finding in electrophysiology, as well as gives a clue to identify a new excitable element of the complex cellular population of neuroblastoma. (C) 2003 Elsevier Science (USA). All rights reserved.