A cluster of cytoplasmic histidine residues specifies pH dependence of the AE2 plasma membrane anion exchanger

A study on the regulatory mechanism of the nonerythroid anion exchanger AE2 by the intracellular protons, reveals its high sensitivity to intracellular pH. The intracellular pH sensor is determined to be the four histidine residues inside the N-terminal, cytoplasmic domain of the pH-sensitive AE2 and AE3 exchangers. This domain is not found in the erythroid anion exchanger. The determined pH sensitivity AE2 and AE3 are consistent with their physiological activities. A new feedback mechanism is also proposed involving direct control of anion exchangers by intracellular protons.