Na-K-Cl cotransporter

Last updated
solute carrier family 12 member 1
Identifiers
SymbolSLC12A1
Alt. symbolsNKCC2
NCBI gene 6557
HGNC 10910
OMIM 600839
Orthologs 286
RefSeq NM_000338
UniProt Q13621
Other data
Locus Chr. 15 q21.1
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Structures Swiss-model
Domains InterPro
solute carrier family 12 member 2
Identifiers
SymbolSLC12A2
Alt. symbolsNKCC1
NCBI gene 6558
HGNC 10911
OMIM 600840
Orthologs 20283
RefSeq NM_001046
UniProt P55011
Other data
Locus Chr. 5 q23.3
Search for
Structures Swiss-model
Domains InterPro

The Na-K-Cl cotransporter (NKCC) is a transport protein that aids in the 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]

Contents

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 secrete fluids, called exocrine glands. [4] In cells of these organs, NKCC1 is commonly found in the basolateral membrane, [5] 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 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 brain during early development, but not in adulthood. [6] 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 predominantly 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. [7]

NKCC2

NKCC2 is specifically found in cells of the thick ascending limb of the loop of Henle and the macula densa in nephrons, the basic functional units of the kidney. Within these cells, NKCC2 resides in 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 vasopressin stimulates the activity of NKCC2. Vasopressin stimulates sodium chloride reabsorption in the thick ascending limb of the nephron by activating signaling pathways. Vasopressin increases the traffic of NKCC2 to the membrane and phosphorylates some serine and threonine sites on the cytoplasmic N-terminal of the NKCC2 located in the membrane, increasing its activity. Increased NKCC2 activity aids in water reabsorption in the collecting duct through 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 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-dependent 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. 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

Related Research Articles

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient.

<span class="mw-page-title-main">Distal convoluted tubule</span>

The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.

<span class="mw-page-title-main">Renal physiology</span> Study of the physiology of the kidney

Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.

<span class="mw-page-title-main">Loop of Henle</span> Part of kidney tissue

In the kidney, the loop of Henle is the portion of a nephron that leads from the proximal convoluted tubule to the distal convoluted tubule. Named after its discoverer, the German anatomist Friedrich Gustav Jakob Henle, the loop of Henle's main function is to create a concentration gradient in the medulla of the kidney.

<span class="mw-page-title-main">Loop diuretic</span> Diuretics that act at the ascending limb of the loop of Henle in the kidney

Loop diuretics are diuretics that act on the Na-K-Cl cotransporter along the thick ascending limb of the loop of Henle in nephrons of the kidneys. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.

<span class="mw-page-title-main">Cotransporter</span>

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable coupled or cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

<span class="mw-page-title-main">Gitelman syndrome</span> Medical condition

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. The disorder is caused by disease-causing variants in both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney. The distal convoluted tubule of the kidney plays an important homeostatic role in sodium and chloride absorption as well as of the reabsorption of magnesium and calcium.

<span class="mw-page-title-main">Bartter syndrome</span> Medical condition

Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.

In the physiology of the kidney, tubuloglomerular feedback (TGF) is a feedback system inside the kidneys. Within each nephron, information from the renal tubules is signaled to the glomerulus. Tubuloglomerular feedback is one of several mechanisms the kidney uses to regulate glomerular filtration rate (GFR). It involves the concept of purinergic signaling, in which an increased distal tubular sodium chloride concentration causes a basolateral release of adenosine from the macula densa cells. This initiates a cascade of events that ultimately brings GFR to an appropriate level.

Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron. They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron. If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

<span class="mw-page-title-main">Sodium-chloride symporter</span> Protein-coding gene in the species Homo sapiens

The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.

In molecular biology, the electroneutral cation-Cl family of proteins are a family of solute carrier proteins. This family includes the products of the Human genes: SLC12A1, SLC12A1, SLC12A2, SLC12A3, SLC12A4, SLC12A5, SLC12A6, SLC12A7, SLC12A8 and SLC12A9.

<span class="mw-page-title-main">Ascending limb of loop of Henle</span>

Within the nephron of the kidney, the ascending limb of the loop of Henle is a segment of the heterogenous loop of Henle downstream of the descending limb, after the sharp bend of the loop. This part of the renal tubule is divided into a thin and thick ascending limb; the thick portion is also known as the distal straight tubule, in contrast with the distal convoluted tubule downstream.

<span class="mw-page-title-main">WNK1</span>

WNK , also known as WNK1, is an enzyme that is encoded by the WNK1 gene. WNK1 is serine-threonine protein kinase and part of the "with no lysine/K" kinase WNK family. The predominant role of WNK1 is the regulation of cation-Cl− cotransporters (CCCs) such as the sodium chloride cotransporter (NCC), basolateral Na-K-Cl symporter (NKCC1), and potassium chloride cotransporter (KCC1) located within the kidney. CCCs mediate ion homeostasis and modulate blood pressure by transporting ions in and out of the cell. WNK1 mutations as a result have been implicated in blood pressure disorders/diseases; a prime example being familial hyperkalemic hypertension (FHHt).

<span class="mw-page-title-main">Chloride potassium symporter 5</span> Protein-coding gene in the species Homo sapiens

Potassium-chloride transporter member 5 is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentrations. It is a critical mediator of synaptic inhibition, cellular protection against excitotoxicity and may also act as a modulator of neuroplasticity. Potassium-chloride transporter member 5 is also known by the names: KCC2 for its ionic substrates, and SLC12A5 for its genetic origin from the SLC12A5 gene in humans.

<span class="mw-page-title-main">Chloride potassium symporter 4</span> Protein-coding gene in the species Homo sapiens

Potassium-chloride transporter, member 4 is a chloride potassium symporter protein. It is encoded by the gene SLC12A4.

The chloride potassium symporter is a membrane transport protein of the solute carrier family 12 that is present in the S3-segment of the renal proximal tubule and in the neuron. It functions in renal chloride reabsorption to transport chloride across the basolateral membrane. Chloride potassium symporter can lower intracellular chloride concentrations below the electrochemical equilibrium potential.

<span class="mw-page-title-main">Electroneutral sodium bicarbonate exchanger 1</span>

Electroneutral sodium bicarbonate exchanger 1 is a protein that in humans is encoded by the SLC4A8 gene.

<span class="mw-page-title-main">SLC12A6</span>

Solute carrier family 12 member 6 is a protein that in humans is encoded by the SLC12A6 gene.

The cation-chloride cotransporter (CCC) family is part of the APC superfamily of secondary carriers. Members of the CCC family are found in animals, plants, fungi and bacteria. Most characterized CCC family proteins are from higher eukaryotes, but one has been partially characterized from Nicotiana tabacum, and homologous ORFs have been sequenced from Caenorhabditis elegans (worm), Saccharomyces cerevisiae (yeast) and Synechococcus sp.. The latter proteins are of unknown function. These proteins show sequence similarity to members of the APC family. CCC family proteins are usually large, and possess 12 putative transmembrane spanners (TMSs) flanked by large N-terminal and C-terminal hydrophilic domains.

References

  1. ↑ Haas M (October 1994). "The Na-K-Cl cotransporters". Am. J. Physiol. 267 (4 Pt 1): C869–85. doi:10.1152/ajpcell.1994.267.4.C869. PMID   7943281. S2CID   22680398.
  2. ↑ Hebert, SC; Mount, DB; Gamba, G (February 2004). "Molecular physiology of cation-coupled Cl− cotransport: the SLC12 family". Pflügers Archiv: European Journal of Physiology. 447 (5): 580–593. doi:10.1007/s00424-003-1066-3. PMID   12739168. S2CID   21998913.
  3. ↑ Russell, J. M. (January 2000). "Sodium-potassium-chloride cotransport". Physiological Reviews. 80 (1): 211–276. doi:10.1152/physrev.2000.80.1.211. ISSN   0031-9333. PMID   10617769. S2CID   8909659.
  4. ↑ Haas M, Forbush B (2000). "The Na-K-Cl cotransporter of secretory epithelia". Annu. Rev. Physiol. 62: 515–34. doi:10.1146/annurev.physiol.62.1.515. PMID   10845101.
  5. 1 2 Delpire E, Lu J, England R, Dull C, Thorne T (June 1999). "Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter". Nat. Genet. 22 (2): 192–5. doi:10.1038/9713. PMID   10369265. S2CID   23779936.
  6. ↑ Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, Delpire E, Jensen FE, Staley KJ (November 2005). "NKCC1 transporter facilitates seizures in the developing brain". Nat. Med. 11 (11): 1205–13. doi:10.1038/nm1301. PMID   16227993. S2CID   25348736.
  7. ↑ Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R (October 2007). "GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations". Physiol. Rev. 87 (4): 1215–84. doi:10.1152/physrev.00017.2006. PMID   17928584.
  8. ↑ Lytle C, Xu JC, Biemesderfer D, Forbush B (December 1995). "Distribution and diversity of Na-K-Cl cotransport proteins: a study with monoclonal antibodies". Am. J. Physiol. 269 (6 Pt 1): C1496–505. doi:10.1152/ajpcell.1995.269.6.C1496. PMID   8572179.
  9. ↑ Gamba G, Friedman PA (May 2009). "Thick ascending limb: the Na(+):K (+):2Cl (-) co-transporter, NKCC2, and the calcium-sensing receptor, CaSR". Pflügers Arch. 458 (1): 61–76. doi:10.1007/s00424-008-0607-1. PMC   3584568 . PMID   18982348.
  10. ↑ Rieg T, Tang T, Uchida S, Hammond HK, Fenton RA, Vallon V (January 2013). "Adenylyl cyclase 6 enhances NKCC2 expression and mediates vasopressin-induced phosphorylation of NKCC2 and NCC". Am. J. Pathol. 182 (1): 96–106. doi:10.1016/j.ajpath.2012.09.014. PMC   3532715 . PMID   23123217.
  11. ↑ Ares GR, Caceres PS, Ortiz PA (December 2011). "Molecular regulation of NKCC2 in the thick ascending limb". Am. J. Physiol. Renal Physiol. 301 (6): F1143–59. doi:10.1152/ajprenal.00396.2011. PMC   3233874 . PMID   21900458.
  12. ↑ Payne JA, Xu JC, Haas M, Lytle CY, Ward D, Forbush B (July 1995). "Primary structure, functional expression, and chromosomal localization of the bumetanide-sensitive Na-K-Cl cotransporter in human colon". J. Biol. Chem. 270 (30): 17977–85. doi: 10.1074/jbc.270.30.17977 . PMID   7629105.
  13. 1 2 Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP (June 1996). "Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2". Nat. Genet. 13 (2): 183–8. doi:10.1038/ng0696-183. PMID   8640224. S2CID   42296304.
  14. ↑ Plata C, Meade P, Vazquez N, Hebert SC, Gamba G (Mar 2002). "Functional properties of the apical Na+-K+-2Cl- cotransporter isoforms". J. Biol. Chem. 277 (13): 11004–12. doi: 10.1074/jbc.M110442200 . PMID   11790783.
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