Na–K–Cl cotransporter

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Na-K-Cl cotransporter
)
solute carrier family 12 member 1
Identifiers
SymbolSLC12A1
Alt. symbolsNKCC2
Chr. 15 q21.1
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StructuresSwiss-model
DomainsInterPro
solute carrier family 12 member 2
Identifiers
SymbolSLC12A2
Alt. symbolsNKCC1
Chr. 5 q23.3
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StructuresSwiss-model
DomainsInterPro

The Na–K–Cl

secondary active transport of sodium, potassium, and chloride into cells.[1] In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes (SLC12A2 and SLC12A1 respectively). Two isoforms of the NKCC1/Slc12a2 gene result from keeping (isoform 1) or skipping (isoform 2) exon 21 in the final gene product.[2]

NKCC1 is widely distributed throughout the human body; it has important functions in

organs that secrete fluids. It is found specifically in the kidney, where it extracts sodium, potassium, and chloride from the urine so 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, they 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 transported solutes is 1Na:1K:2Cl. However, there is a notable exception in squid giant axon as the symporter in this special cell has a stoichiometry of 2Na:1K:3Cl, although electroneutrality is still maintained.[3]

NKCC1

NKCC1 is widely distributed throughout the body, especially in organs that

concentration of solutes and causing water to be secreted 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.[5]

NKCC1 is also expressed in many regions of the

K-Cl cotransporter increased, thus bringing internal chloride concentration in neurons down to adult values.[7]

NKCC2

NKCC2 is specifically found in cells of the

apical membrane[8] abutting the nephron's lumen, which is the hollow space containing urine. It thus serves both in sodium absorption and in tubuloglomerular feedback
.

The thick ascending limb of the loop of Henle begins at the deeper portion of the renal outer medulla. Here, the urine has a relatively high concentration of sodium. As urine moves towards the more superficial portion of the thick ascending limb, NKCC2 is the major transport protein by which sodium is reabsorbed from the urine. This outward movement of sodium and the lack of water permeability in the thick ascending limb, creates a more diluted urine.[9] According to the stoichiometry outlined above, each sodium ion reabsorbed brings one potassium ion and two chloride ions. 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. The action of these loop diuretics also reduces potassium reabsorption through the NKCC2 cotransporter and consequently increases tubular flow rate which enhances potassium secretion and emphasises the hypokalaemic effect.

Impaired sodium reabsorption increases diuresis by three mechanisms:

  1. Increases the amount of active osmolytes in urine by decreasing absorption of sodium
  2. Erases the papillar gradient
  3. Inhibits tubuloglomerular feedback

Loop diuretics therefore ultimately result in decreased blood pressure.

The hormone

aquaporin 2 channels by creating a hypo-osmotic filtrate.[10][11]

Genetics

NKCC1 and NKCC2 are encoded by genes on the long arms of chromosomes 5[12] and 15,[13] respectively. A loss of function mutation of NKCC2 produces Bartter syndrome, an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis with normal to low blood pressure.[13]

Kinetics

The

secondary active transport
. There are three isoforms of NKCC2 created by alternative splicing (NKCC2A, B and F). Each one of these isoforms is expressed at different portions of the thick ascending limb and they have different affinity for sodium that correlates with its localization. The isoform F is more predominant in the deeper portion of the thick ascending limb, where the sodium concentration is very high. NKCC2F is the isoform with the lowest affinity for sodium and this allows the cotransporter to work at this sodium rich environment. Conversely, NKCC2B is expressed at the more superficial portion of the thick ascending limb and the macula densa, and it has the highest affinity for sodium. This permits NKCC2B to function in this sodium-depleted environment without saturating. The NKCC2A isoform shows an intermediate distribution and affinity for sodium.[14] In this way, NKCC2 is able to function properly along the range of sodium concentrations found along the thick ascending limb.

See also

References

External links