Mn is an essential component of the oxygen-evolving machinery of photosynthesis and is an essential cofactor of several important enzymes, such as Mn-superoxide dismutase and Mn-catalase. The availability of Mn in the environment varies, and little is known about the mechanisms for maintaining cytoplasmic Mn(2+) ion homeostasis. Using a DNA microarray, we screened knockout libraries of His kinases and response regulators of Synechocystis sp PCC 6803 to identify possible participants in this process. We identified a His kinase, ManS, which might sense the extracellular concentration of Mn(2+) ions, and a response regulator, ManR, which might regulate the expression of the mntCAB operon for the ABC-type transporter of Mn(2+) ions. Furthermore, analysis with the DNA microarray and by reverse transcription PCR suggested that ManS produces a signal that activates ManR, which represses the expression of the mntCAB operon. At low concentrations of Mn(2+) ions, ManS does not generate a signal, with resulting inactivation of ManR and subsequent expression of the mntCAB operon.