Intracellular pH regulation by acid-base transporters in mammalian neurons

Intracellular pH (pH(i)) regulation in the brain is important in both physiological and physiopathological conditions because changes in pH(i) generally result in altered neuronal excitability. In this review, we will cover 4 major areas: (1) The effect of pH(i) on cellular processes in the brain, including channel activity and neuronal excitability. (2) pH(i) homeostasis and how it is determined by the balance between rates of acid loading (J(L)) and extrusion (J(E)). The balance between J(E) and J(L) determine steady-state pH(i), as well as the ability of the cell to defend pH(i) in the face of extracellular acid-base disturbances (e.g., metabolic acidosis). (3) The properties and importance of members of the SLC4 and SLC9 families of acid-base transporters expressed in the brain that contribute to J(L) (namely the Cl-HCO(3) exchanger AE3) and J(E) (the Na-H exchangers NHE1, NHE3, and NHE5 as well as the Na(+)- coupled HCO(3)(−) transporters NBCe1, NBCn1, NDCBE, and NBCn2). (4) The effect of acid-base disturbances on neuronal function and the roles of acid-base transporters in defending neuronal pH(i) under physiopathologic conditions.