The plasma membrane Na + ⁄H + exchanger 1 is activated in response to various extrinsic factors, and this process is regulated by an intracellular pH-sensing mechanism. To identify the candidate residues responsible for intracellular pH regulation, we analyzed the functional properties of engi-neered Na + ⁄H + exchanger 1 mutants with charge-reversal mutations of charged residues located in the intracellular loops.