Na-K-Cl cotransporter

The Na-K-Cl cotransporter (NKCC, SLC12A2) is a protein that aids in the active transport of sodium, potassium, and chloride into and out of cells. There are two varieties, or isoforms, of this membrane transport protein, called NKCC1 and NKCC2. NKCC1 is widely distributed throughout the body; it has important functions in organs that secrete fluids. NKCC2 is found specifically in the kidney, where it serves to extract sodium, potassium, and chloride from the urine so that they can be reabsorbed into the blood.

Function
NKCC proteins are membrane transport proteins that transport sodium (Na), potassium (K), and chloride (Cl) ions across the cell membrane. Because they move each solute in the same direction, NKCC proteins are considered symporters. They maintain electroneutrality by moving two positively charged solutes (sodium and potassium) alongside two parts of a negatively charged solute (chloride). Thus the stoichiometry of the NKCC proteins is 1Na:1K:2Cl.

NKCC1
NKCC1 is widely distributed throughout the body, especially in organs that secrete fluids, called exocrine glands. In cells of these organs, NKCC1 is commonly found in the basolateral membrane, the part of the cell membrane closest to the blood vessels. Its basolateral location gives NKCC1 the ability to transport sodium, potassium, and chloride from the blood into the cell. Other transporters assist in the movement of these solutes out of the cell through its apical surface. The end result is that solutes from the blood, particularly chloride, are secreted into the lumen of these exocrine glands, increasing the luminal concentration of solutes and causing water to be secreted as well by osmosis.

In addition to exocrine glands, NKCC1 is necessary for establishing the potassium-rich endolymph that bathes part of the cochlea, an organ necessary for hearing. Inhibition of NKCC1, as with furosemide or other loop diuretics, can result in deafness.

NKCC1 is also expressed in many regions of the brain during early development, but not in adulthood. This change in NKCC1 presence seems to be responsible for altering responses to the neurotransmitters GABA and glycine from excitatory to inhibitory, which was suggested to be important for early neuronal development. As long as NKCC1 transporters are predominantely active, internal chloride concentrations in neurons is raised in comparison with mature chloride concentrations, which is important for GABA and glycine responses, as respective ligand-gated anion channels are permeable to chloride. With higher internal chloride concentrations, outward driving force for this ions increases, and thus channel opening leads to chloride leaving the cell, thereby depolarizing it. Put another way, increasing internal chloride concentration increases the reversal potential for chloride, given by the Nernst equation. Later in development expression of NKCC1 is reduced, while expression of a KCC2 K-Cl cotransporter - increased, thus bringing internal chloride concentration in neurons down to adult values.

NKCC2
NKCC2 is specifically found in cells of the thick ascending limb of the loop of Henle in nephrons, the basic functional units of the kidney. Within these cells, NKCC2 resides in the apical membrane abutting the nephron's lumen, the hollow space containing urine.

Urine in the thick ascending limb of the loop of Henle has a relatively high concentration of sodium. That is, the electrochemical gradient of sodium favors movement of sodium from the urine and into cells. At this region of the nephron, NKCC2 is the major transport protein by which sodium is reabsorbed from the urine and into cells. According to the stoichiometry outlined above, each molecule of sodium reabsorbed brings one molecule of potassium and two molecules of chloride. Sodium goes on to be reabsorbed into the blood, where it contributes to the maintenance of blood pressure.

Furosemide and other loop diuretics inhibit the activity of NKCC2, thereby impairing sodium reabsorption in the thick ascending limb of the loop of Henle. Impaired sodium reabsorption prevents the thick ascending limb from contributing to maintenance of blood pressure. Loop diuretics therefore ultimately result in decreased blood pressure.

Genetics
NKCC1 and NKCC2 are encoded by genes on the long arms of chromosomes 15 and 5, respectively.

Kinetics
The energy required to move solutes across the cell membrane is provided by the electrochemical gradient of sodium. Sodium's electrochemical gradient is established by the Na-K ATPase, which is an ATP-requiring enzyme. Since NKCC proteins use sodium's gradient, their activity is indirectly dependent on ATP; for this reason, NKCC proteins are said to move solutes by way of secondary active transport.