Ethanol is known to be neurotoxic. Protective mechanisms, however, are activated upon ethanol induction of the glucose-regulated stress proteins (GRPs), GRP78 and GRP94. These endoplasmic reticulum-residing chaperones are known to be involved in channel subunit assembly. The GRP and human-ether-à-gogo-related gene (HERG) K(+)-channel expression were monitored in short- and long-term ethanol incubation experiments using the human neuroblastoma cell line SH-SY5Y. mRNA of the stress proteins and protein levels of the GRPs and HERG were determined using Northern and Western blot methods. Short-term ethanol incubation caused a transient increase of GRP transcripts. Protein levels of GRP94 decreased in chronic experiments, whereas GRP78 did not change. HERG followed the same kinetics as GRP94 with a constant down-regulation. The coordinate down-regulation of GRP94 and HERG implies the specific involvement of the endoplasmic reticulum chaperone GRP94 and HERG, but not GRP78, in a process of cell adaptation.