Intracellular pH regulation in the brain is extremely important under both physiological and physiopathological conditions. Changes in intracellular pH often result in altered neuronal excitability. In mammalian cells, intracellular pH against acidosis is generally regulated by ion transporters located in the plasma membrane called sodium-hydrogen exchangers (Na⁺/H⁺ exchanger, NHE)¹.
 
Several studies have suggested that Na⁺/H⁺ exchange is the predominant pH-regulatory mode in isolated nerve terminals. Na⁺/H⁺ exchanger also has a role in the regulation of synaptic transmission at glutamatergic, GABAergic, and dopaminergic synapses. In addition, NHE transporters also function in a coupled mode to mediate recovery from decreased cell volume¹.
 
The NHE family belongs to the Slc9 gene family of Na⁺ coupled transport proteins and comprises nine mammalian isoforms of Na⁺/H⁺ exchangers that are localized to the plasma membrane. NHE1-9 are encoded by the SLC9A1-SLC9A9 genes, respectively.
 
The structure of SLC9 family members includes a short N-terminus and an extensive C-terminus that plays a regulatory role.
 
NHE-5 exchanger corrects intracellular acidosis by exporting H⁺ in exchange for extracellular Na⁺, thereby tending to raise intracellular pH. Several studies have suggested that NHE5 plays a critical role in the synaptic pH regulation during the firing of action potentials¹.
 
It is predominantly detected in the brain with high expression in multiple regions such as the hippocampus and cerebral cortex³. 
 
NHE5 knockdown or overexpression of a dominant-negative mutation of NHE5 in cultured hippocampal neurons causes dendritic spine overgrowth. Therefore it has been suggested that NHE5 acts as a negative regulator of activity-dependent spine growth by regulating pH-sensitive synaptic proteins^2,3.