Retinoic acid-induced differentiation of SH-SY5Y human neuroblastoma cells results in the development of extensive neurite processes as well as changes in cell body morphology toward a neuronal phenotype. The authors have examined concurrent regulation of beta-amyloid precursor protein (APP) and inositol 1,4,5-trisphosphate receptor (insP(3)R) gene expression in SY5Y cells during neuronal differentiation. Of the multiple APP mRNA transcripts expressed in this cell line, retinoic acid treatment significantly increased the expression of APP(695) transcript while the level of total APP remained unchanged. In the same time course, neuronal differentiation decreased the expression of insP(3)R at both the mRNA and protein levels. These findings demonstrate an inverse relationship between APP and insP(3)R gene expression during neuronal differentiation of SH-SY5Y cells and suggest a possible change in intracellular calcium homeostasis.