Structural features underlying retention of the SERCA pump in intracellular compartments and the sorting of the PMCA pump to the plasma membrane are not known. The biochemical properties of the two pumps suggest that their differential localization may respond to specific functional demands. The two pumps may control Ca(2+) gradients of different magnitude and dynamic properties. For instance, it has recently become clear that the Ca(2+) gradient across the endoplasmic reticulum (ER) membrane is smaller than that across the plasma membrane. Previous experiments with chimerical constructs of the SERCA and PMCA pumps had suggested a role for the amino-terminal domain in the ER retention of the SERCA pump. Experiments aimed at narrowing down the region responsible for the retention now indicate that the first 28 amino acids of the SERCA pump may play a role in membrane localization. Results also suggest that the formation of oligomers (possibly through the first 28 amino acids) might be critical to the retention mechanism.