Na+/K+/Cl- Symporter

Na+/K+/Cl- Symporters (NKCC) are membrane-bound channels that play a prominent role in a variety of epithelial absorptive and secretory processes and a direct role in cell volume regulation and possibly in cell cycle regulation. NKCCs are members of the SLC12 family of cation-coupled chloride transportersand there are two NKCC isoforms, NKCC1 and NKCC2. NKCC1 is found on almost all cells types and, importantly, is located on the basolateral membrane of secretory epithelia. In contrast NKCC2 is found exclusively in the kidney, specifically on the apical membrane of absorptive epithelia.

The NKCC is distinguished from all other transporters by the fact that it transports Na⁺, K⁺ and Cl^- stoichiometrically by means of a tightly coupled mechanism that can be blocked by loop diuretics. The NKCC is electrically silent (i.e. not driven by a membrane voltage, nor does it establish one) and requires all three ions to be simultaneously present on the same side of the plasma membrane. This is achieved by an allosteric effect where binding of one ion increases the apparent affinity of the binding site for the other ions. NH₄⁺ may substitute for K⁺ (especially at NKCC2), which has an important role in NH₄⁺ recycling and excretion of excess acid in the kidney.

The NKCC involves a secondary active transport process, despite its requirement for cellular ATPase. It is activated by phosphorylation, which is mediated by PKC and PKA. CK2 binding sites are also present on the NKCC, but the significance is unknown. Protein phosphatases act to reduce NKCC activity by dephosphorylating the transporter. Furthermore, the intracellular concentration of ions, including Cl^-, Na⁺, K⁺, Mg²⁺, Ca²⁺ and H⁺, has an effect on NKCC activity. There is also evidence that depolymerization of the actin cytoskeleton is associated with NKCC activation.

External sources of pharmacological information for Na+/K+/Cl- Symporter :

• IUPHAR Receptor Code

• BJP Guide

Na+/K+/Cl- Symporter Gene Data