Maintaining physiological intracellular pH values is vital for most cells. The Na⁺/H⁺ exchanger family (NHE, also known as SLC9) is widely expressed and has a key role in protecting cells against acidification. There are currently six NHE transporters identified in mammalian cells¹.
 
The complete structure of members of the NHE family has not been completely solved. However, all members are organized in a similar manner with 11 or 12 membrane spanning domains, carrying out the Na⁺ and H⁺ exchange and a varying length intracellular C-terminal domain being involved in regulation of the exchange activity. The transport of Na⁺ and H⁺ in NHEs occurs in the center of the N-terminus via a two inverted funnel area that is made up of two transmembrane regions.
 
NHE3 is expressed in sodium absorptive cells of the mammalian small intestine, colon, gall bladder, renal proximal tubule, and thick and thin limbs of the loop of Henle and can be mostly found in the plasma membrane².
 
NHE3 interacts with a multi-PDZ domain-containing scaffold protein called NHERF-1. NHERF-1 binds to the NHE3 C-terminus and has a role in NHE3 regulation in various cells. NHERF-1 functions as a cofactor required for the phosphorylation and downregulation of NHE3 activity in response to elevated intracellular cAMP³. In addition, silencing of NHERF-1 in a model of diabetic mice was found to prevent NHE3 trafficking and insulin-dependent activation⁴.