The plasma membrane calcium pump (PMCA) and sarco(endo)plasmic reticular calcium pump (SERCA) are important components of the Ca2+ homeostasis system responsible for intracellular Ca2+ signaling, yet the factors which govern their expression remain unclear. Recently, we have found that overexpression of PMCA by a gene transfection approach caused a down-regulation of the SERCA pump [Liu B.F., Xu X., Fridman R., Muallem S., Kuo T.H. Consequences of functional expression of the plasma membrane calcium pump isoform 1a. J Biol Chem 1996; 271: 5536-5544]. The results suggest an interdependence between PMCA and SERCA gene expression which has prompted us to investigate further on the mechanisms that regulate the expression of these Ca2+ pump genes in various cultured cell lines. In the present study, we have analyzed the isoforms of the PMCA and SERCA in different cells and presented evidence in favor of a co-induction of the PMCA and SERCA gene expression by second messengers, such as protein kinase C, cAMP, and Ca2+. Ectopic expression of PMCA or SERCA led to downregulation of the endogenous forms of both pumps. Changes in the level of mRNAs were paralleled by corresponding altered pump protein contents. The Ca(2+)-mediated increase of gene expression is accompanied by increased transcription rates as indicated by nuclear run-on assay. The co-ordinated induction of the PMCA and SERCA gene expression by thapsigargin was not blocked by the cytosolic application of the Ca2+ chelator BAPTA. We conclude that genes encoding components of the major Ca2+ transport pathways, including pumps and IP3 receptor channels, are regulatorally linked and this link is provided by the Ca2+ load of the ER store. This study points to the importance of gene expression as an integral component in the regulation of cellular Ca2+ homeostasis.