View source for Biology:Na-K-Cl cotransporter

{{Short description|Group of transport proteins}}
{{infobox protein
| Name = solute carrier family 12 member 1
| caption = 
| image = 
| width = 
| HGNCid = 10910
| Symbol = SLC12A1
| AltSymbols = NKCC2
| EntrezGene = 6557
| OMIM = 600839
| HomoloGene = 286
| RefSeq = NM_000338
| UniProt = Q13621
| PDB = 
| ECnumber = 
| Chromosome = 15
| Arm = q
| Band = 21.1
| LocusSupplementaryData =
}}
{{infobox protein
| Name = solute carrier family 12 member 2
| caption = 
| image = 
| width = 
| HGNCid = 10911
| Symbol = SLC12A2
| AltSymbols = NKCC1
| EntrezGene = 6558
| OMIM = 600840
| HomoloGene = 20283
| RefSeq = NM_001046
| UniProt = P55011
| PDB = 
| ECnumber = 
| Chromosome = 5
| Arm = q
| Band = 23.3
| LocusSupplementaryData = 
}}

The '''Na-K-Cl [[Physics:Cotransporter|cotransporter]]''' ('''NKCC''') is a [[Biology:Transport protein|transport protein]] that aids in the secondary active transport of [[Chemistry:Sodium|sodium]], [[Chemistry:Potassium|potassium]], and [[Chemistry:Chloride|chloride]] into [[Biology:Cell|cells]].<ref name="pmid7943281">{{cite journal | vauthors = Haas M | title = The Na-K-Cl cotransporters | journal = Am. J. Physiol. | volume = 267 | issue = 4 Pt 1 | pages = C869–85 | date=October 1994 | pmid = 7943281 | doi = 10.1152/ajpcell.1994.267.4.C869 | s2cid = 22680398 }}</ref> In humans there are two isoforms of this [[Biology:Membrane transport protein|membrane transport protein]], '''NKCC1''' and '''NKCC2''', encoded by two different [[Biology:Gene|gene]]s (''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.<ref>{{cite journal|last=Hebert|first=SC|author2=Mount, DB|author3= Gamba, G|title=Molecular physiology of cation-coupled Cl<sup>−</sup> cotransport: the SLC12 family.|journal=Pflügers Archiv: European Journal of Physiology|date=February 2004 |volume=447|issue=5|pages=580–593|doi=10.1007/s00424-003-1066-3|pmid=12739168|s2cid=21998913}}</ref>

NKCC1 is widely distributed throughout the human body; it has important functions in [[Biology:Organ (anatomy)|organs]] that [[Biology:Secretion|secrete]] fluids. It is found specifically in the kidney, where it extracts sodium, potassium, and chloride from the [[Biology:Urine|urine]] so they can be reabsorbed into the [[Biology:Blood|blood]].

==Function==
NKCC proteins are [[Biology:Membrane transport protein|membrane transport protein]]s that transport [[Chemistry:Sodium|sodium]] (Na), [[Chemistry:Potassium|potassium]] (K), and [[Chemistry:Chloride|chloride]] (Cl) ions across the [[Biology:Cell membrane|cell membrane]]. Because they move each solute in the same direction, they are considered [[Biology:Symporter|symporter]]s. They maintain electroneutrality by moving two positively charged solutes (sodium and potassium) alongside two parts of a negatively charged solute (chloride). Thus the [[Chemistry:Stoichiometry|stoichiometry]] of the transported solutes is 1Na:1K:2Cl. However, there is a notable exception in [[Biology:Squid giant axon|squid giant axon]] as the symporter in this special cell has a stoichiometry of 2Na:1K:3Cl, although electroneutrality is still maintained.<ref>{{Cite journal|last=Russell|first=J. M.|date=January 2000|title=Sodium-potassium-chloride cotransport|journal=Physiological Reviews|volume=80|issue=1|pages=211–276|doi=10.1152/physrev.2000.80.1.211|issn=0031-9333|pmid=10617769|s2cid=8909659|url=https://semanticscholar.org/paper/f3b1795d2c69f48ac7166f3a3def09351a790b20}}</ref>

===NKCC1===
NKCC1 is widely distributed throughout the body, especially in organs that [[Biology:Secretion|secrete]] fluids, called exocrine glands.<ref name="pmid10845101">{{cite journal |vauthors=Haas M, Forbush B | title = The Na-K-Cl cotransporter of secretory epithelia | journal = Annu. Rev. Physiol. | volume = 62 | pages = 515–34 | year = 2000 | pmid = 10845101 | doi = 10.1146/annurev.physiol.62.1.515  }}</ref> In cells of these organs, NKCC1 is commonly found in the basolateral membrane,<ref name="pmid10369265"/> the part of the [[Biology:Cell membrane|cell membrane]] closest to the [[Biology:Blood vessel|blood vessel]]s. 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 [[Physics:Osmosis|osmosis]].

In addition to exocrine glands, NKCC1 is necessary for establishing the potassium-rich [[Biology:Endolymph|endolymph]] that bathes part of the [[Medicine:Cochlea|cochlea]], an organ necessary for hearing. Inhibition of NKCC1, as with [[Biology:Furosemide|furosemide]] or other loop diuretics, can result in [[Medicine:Deafness|deafness]].<ref name="pmid10369265">{{cite journal |vauthors = Delpire E, Lu J, England R, Dull C, Thorne T | title = Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter | journal = Nat. Genet. | volume = 22 | issue = 2 | pages = 192–5 | date=June 1999 | pmid = 10369265 | doi = 10.1038/9713  | s2cid = 23779936 }}</ref>

NKCC1 is also expressed in many regions of the [[Biology:Brain|brain]] during early development, but not in adulthood.<ref name="pmid16227993">{{cite journal |vauthors=Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, Delpire E, Jensen FE, Staley KJ | title = NKCC1 transporter facilitates seizures in the developing brain | journal = Nat. Med. | volume = 11 | issue = 11 | pages = 1205–13 | date=November 2005 | pmid = 16227993 | doi = 10.1038/nm1301  | s2cid = 25348736 }}</ref> This change in NKCC1 presence seems to be responsible for altering responses to the neurotransmitters GABA and [[Chemistry:Glycine|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 [[Biology:Reversal potential|reversal potential]] for chloride, given by the [[Physics:Nernst equation|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.<ref name="pmid17928584">{{cite journal | vauthors = Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R | title = GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations | journal = Physiol. Rev. | volume = 87 | issue = 4 | pages = 1215–84 | date = October 2007 | pmid = 17928584 | doi = 10.1152/physrev.00017.2006  }}</ref>

===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<ref name="pmid8572179">{{cite journal |vauthors=Lytle C, Xu JC, Biemesderfer D, Forbush B | title = Distribution and diversity of Na-K-Cl cotransport proteins: a study with monoclonal antibodies | journal = Am. J. Physiol. | volume = 269 | issue = 6 Pt 1 | pages = C1496–505 | date=December 1995 | pmid = 8572179 | doi = 10.1152/ajpcell.1995.269.6.C1496 }}</ref> abutting the nephron's [[Biology:Lumen (anatomy)|lumen]], which is the hollow space containing [[Biology:Urine|urine]]. It thus serves both in sodium absorption and in [[Biology:Tubuloglomerular feedback|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.<ref name="pmid18982348">{{cite journal |vauthors=Gamba G, Friedman PA | title = Thick ascending limb: the Na(+):K (+):2Cl (-) co-transporter, NKCC2, and the calcium-sensing receptor, CaSR | journal = Pflügers Arch | volume = 458 | issue = 1 | pages = 61–76 | date=May 2009 | pmid = 18982348 | doi = 10.1007/s00424-008-0607-1| pmc=3584568}}</ref> 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 [[Biology:Blood|blood]], where it contributes to the maintenance of [[Physics:Blood pressure|blood pressure]].

[[Biology:Furosemide|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:
# Increases the amount of active [[Physics:Osmolyte|osmolyte]]s in urine by decreasing absorption of sodium
# Erases the papillar gradient
# Inhibits [[Biology:Tubuloglomerular feedback|tubuloglomerular feedback]] 
Loop diuretics therefore ultimately result in decreased blood pressure.

The hormone [[Biology:Vasopressin|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 [[Chemistry:Serine|serine]] and [[Chemistry:Threonine|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 [[Biology:Aquaporin 2|aquaporin 2]] channels by creating a hypo-osmotic filtrate.<ref name="pmid23123217">{{cite journal | vauthors = Rieg T, Tang T, Uchida S, Hammond HK, Fenton RA, Vallon V | title = Adenylyl cyclase 6 enhances NKCC2 expression and mediates vasopressin-induced phosphorylation of NKCC2 and NCC | journal = Am. J. Pathol. | volume = 182 | issue = 1 | pages = 96–106 | date = January 2013 | pmid = 23123217 | pmc = 3532715 | doi = 10.1016/j.ajpath.2012.09.014 }}</ref><ref name="pmid21900458">{{cite journal | vauthors = Ares GR, Caceres PS, Ortiz PA | title = Molecular regulation of NKCC2 in the thick ascending limb | journal = Am. J. Physiol. Renal Physiol. | volume = 301 | issue = 6 | pages = F1143–59 | date = December 2011 | pmid = 21900458 | pmc = 3233874 | doi = 10.1152/ajprenal.00396.2011 }}</ref>

==Genetics==
NKCC1 and NKCC2 are encoded by [[Biology:Gene|gene]]s on the [[Biology:Locus (genetics)|long arms]] of [[Biology:Chromosome 5|chromosomes 5]]<ref name="pmid7629105">{{cite journal |vauthors=Payne JA, Xu JC, Haas M, Lytle CY, Ward D, Forbush B | title = Primary structure, functional expression, and chromosomal localization of the bumetanide-sensitive Na-K-Cl cotransporter in human colon | journal = J. Biol. Chem. | volume = 270 | issue = 30 | pages = 17977–85 | date=July 1995 | pmid = 7629105 | doi = 10.1074/jbc.270.30.17977  | doi-access = free }}</ref> and [[Biology:Chromosome 15|15]],<ref name="pmid8640224">{{cite journal |vauthors = Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP | title = Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2 | journal = Nat. Genet. | volume = 13 | issue = 2 | pages = 183–8 | date=June 1996 | pmid = 8640224 | doi = 10.1038/ng0696-183  | s2cid = 42296304 }}</ref> respectively.  A loss of function mutation of NKCC2 produces [[Medicine:Bartter syndrome|Bartter syndrome]], an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis with normal to low blood pressure.<ref name="pmid8640224"/>

==Kinetics==
The [[Physics:Energy|energy]] required to move solutes across the cell membrane is provided by the [[Biology:Electrochemical gradient|electrochemical gradient]] of sodium. Sodium's electrochemical gradient is established by the Na-K ATPase, which is an [[Chemistry:Adenosine triphosphate|ATP]]-dependent [[Biology:Enzyme|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.<ref name="pmid11790783">{{cite journal |vauthors=Plata C, Meade P, Vazquez N, Hebert SC, Gamba G | title = Functional properties of the apical Na+-K+-2Cl- cotransporter isoforms | journal = J. Biol. Chem. | volume = 277 | issue = 13 | pages = 11004–12 | date=Mar 2002 | pmid = 11790783 | doi = 10.1074/jbc.M110442200 | doi-access = free }}</ref> In this way, NKCC2 is able to function properly along the range of sodium concentrations found along the thick ascending limb.

==See also==
*Cotransport
*[[Physics:Cotransporter|Cotransporter]]

==References==
{{Reflist|2}}

==External links==
* {{MeshName|Sodium-Potassium-Chloride+Symporters}}

{{Ion pumps}}
{{Membrane transport proteins}}

[[Category:Solute carrier family]]

{{Sourceattribution|Na-K-Cl cotransporter|1}}