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The Na-K-Cl cotransporter (NKCC) is a protein that aids in the active transport of sodium, potassium, and chloride into and out of cells.^[1] There are two varieties of this membrane transport protein, NKCC1 and NKCC2, however these are encoded by two different genes (SLC12A2 and SLC12A1 respectively) and are not isoforms. 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 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.^[3] In cells of these organs, NKCC1 is commonly found in the basolateral membrane,^[4] 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.^[4]

NKCC1 is also expressed in many regions of the brain during early development, but not in adulthood.^[5] 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.^[6]

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^[7] 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.

The hormone, Vasopressin, stimulates the activity of NKCC2. Vasopressin stimulates sodium chloride reabsorption in the thick ascending limb of the nephron activating signaling pathways. It increases the traffic of the NKCC2 to the membrane and phosphorylate at some serine and threonine sites the cytoplasmic N-terminal of the NKCC2 located in the membrane, increasing its activity; further aiding in water reabsorption in the collecting duct through Aquaporin 2 channels by the creation of a hypo-osmotic filtrate. ^[8] ^[9]

Genetics

NKCC1 and NKCC2 are encoded by genes on the long arms of chromosomes 15^[10] and 5,^[11] 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.^[11]

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.

References

^ Haas M (October 1994). "The Na-K-Cl cotransporters". Am. J. Physiol. 267 (4 Pt 1): C869–85. PMID 7943281.
^ Hebert, SC; Mount, DB; Gamba, G (Feb 2004). "Molecular physiology of cation-coupled Cl⁻ cotransport: the SLC12 family.". Pflugers Archiv : European journal of physiology 447 (5): 580–593. doi:10.1007/s00424-003-1066-3. PMID 12739168.
^ 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.
^ ^a ^b 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.
^ 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.
^ 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.
^ 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. PMID 8572179.
^ Rieg T1, Tang T, Uchida S, Hammond HK, Fenton RA, Vallon V. (November 2012). "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. PMID 23123217.
^ Ares GR, Caceres PS, Ortiz PA. (September 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. PMID 21900458.
^ 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.
^ ^a ^b 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.

External links

Sodium-Potassium-Chloride Symporters at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. バーター症候群およびギテルマン症候群 bartter and gitelman syndromes
2. 腎でのマグネシウム処理における利尿剤の有効性 effect of diuretics on magnesium handling by the kidney
3. 利尿剤とカルシウムバランス diuretics and calcium balance
4. 赤血球水分量の制御 control of red blood cell hydration
5. カルシウム感知性受容体障害：家族性低カルシウム尿性高カルシウム血症および常染色体優性低カルシウム血症 disorders of the calcium sensing receptor familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia

English Journal

Rare mutations in renal sodium and potassium transporter genes exhibit impaired transport function.

Welling PA.SourceDepartment of Physiology, University of Maryland Medical School, Baltimore, Maryland, USA.
Current opinion in nephrology and hypertension.Curr Opin Nephrol Hypertens.2013 Nov 17. [Epub ahead of print]
PURPOSE OF REVIEW: Recent efforts to explore the genetic underpinnings of hypertension revealed rare mutations in kidney salt transport genes contribute to blood pressure (BP) variation and hypertension susceptibility in the general population. The current review focuses on these latest findings, hi
PMID 24253496

Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension.

Picard N, Trompf K, Yang CL, Miller RL, Carrel M, Loffing-Cueni D, Fenton RA, Ellison DH, Loffing J.SourceInstitute of Anatomy, University of Zurich, Zurich, Switzerland;
Journal of the American Society of Nephrology : JASN.J Am Soc Nephrol.2013 Nov 14. [Epub ahead of print]
The thiazide-sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and arterial BP. Loss-of-function mutations of NCC cause renal salt wasting with arterial hypotension (Gitelman syndrome). Conversely, mutations in the NCC-regulating WNK kinases or k
PMID 24231659

Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.

Trudu M, Janas S, Lanzani C, Debaix H, Schaeffer C, Ikehata M, Citterio L, Demaretz S, Trevisani F, Ristagno G, Glaudemans B, Laghmani K, Dell'antonio G; the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) team, Bochud M, Burnier M, Devuyst O, Martin PY, Mohaupt M, Paccaud F, Pechère-Bertschi A, Vogt B, Ackermann D, Ehret G, Guessous I, Ponte B, Pruijm M, Loffing J, Rastaldi MP, Manunta P, Devuyst O, Rampoldi L.SourceDulbecco Telethon Institute, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Nature medicine.Nat Med.2013 Nov 3. doi: 10.1038/nm.3384. [Epub ahead of print]
Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause inde
PMID 24185693

Japanese Journal

Bartter 症候群と Gitelman 症候群に対する利尿剤負荷試験の有用性についての検討

神田杏子,野津寛大,橋村裕也,貝藤裕史,亀井宏一,中西浩一,吉川徳茂,関根孝司,五十嵐隆,小松博史,宮下律子,飯島一誠,松尾雅文
日本小児腎臓病学会雑誌 = Japanese journal of pediatric nephrology 22(1), 24-28, 2009-04-15
　Bartter症候群 (BS) とGitelman症候群 (GS) は，低K血症，高レニン・アルドステロン血症を特徴とする遺伝性尿細管疾患である。近年，原因部位・遺伝子が特定され，BSは1型から4型まで分類可能となったが，原因遺伝子を特定できる施設は限られており臨床症状や検査所見で分類しているのが現状である。しかし，BS3型はGSと臨床症状や検査所見が類似する患者が存在するため，それのみでは診断 …
NAID 10025170680

Bartter 症候群の病因病態 : 遺伝子解析から見えてきたもの

野津寛大,飯島一誠,松尾雅文
日本小児科学会雑誌 112(7), 1059-1067, 2008-07-01
NAID 10024301353

Novel SLC12A1 (NKCC2) Mutations in Two Families with Bartter Syndrome Type 1

ADACHI MASANORI,ASAKURA YUMI,SATO YOSHIAKI,TAJIMA TOSHIHIRO,NAKAJIMA TAKEO,YAMAMOTO TOSHIYUKI,FUJIEDA KENJI
Endocrine journal 54(6), 1003-1007, 2007-12-01
NAID 10021264098

Related Pictures

★リンクテーブル★

リンク元	「バーター症候群」「Na+-K+-2Cl-共輸送体」

「バーター症候群」

solute carrier family 12 (sodium/potassium/chloride transporters), member 1
Identifiers
Symbol	SLC12A1
Entrez	6558
HUGO	10911
OMIM	600840
RefSeq	NM_001046
UniProt	P55011
Other data
Locus	Chr. 5 q23.3

solute carrier family 12 (sodium/potassium/chloride transporters), member 2
Identifiers
Symbol	SLC12A2
Entrez	6557
HUGO	10910
OMIM	600839
RefSeq	NM_000338
UniProt	Q13621
Other data
Locus	Chr. 15 q15−q21

　　[★]

英: Bartter syndrome, Bartter's syndrome
同: Bartter症候群
関: ギテルマン症候群 Gitelman症候群

概念

常染色体劣性遺伝　AR
RAA系の亢進　にもかかわらず　正常血圧、浮腫の欠如
低カリウム血症、代謝性アルカローシス
傍糸球体細胞の過形成
多飲、多尿　←　アルドステロンのエスケープ現象(尿濃縮脳の障害)。これにより血圧上昇がキャンセル？

ヘンレループ太い上行脚にあるループ利尿薬の標的輸送体の機能異常　→　常にフロセミドが効いた状態と考えてみる。

病因

遺伝子異常

1つは、NKCC2をコードしているSLC12A1の遺伝子異常

原因遺伝子

	Location		Phenotype	Phenotype		Gene/Locus	Gene/Locus
	Location		Phenotype	MIM number			MIM number
1	15q21.1	[[1]]	Bartter syndrome, type 1	601678	[[2]]	SLC12A1	600839	[[3]]
2	11q24.3	[[4]]	Bartter syndrome, type 2	241200	[[5]]	KCNJ1	600359	[[6]]
3	1p36.13	[[7]]	Bartter syndrome, type 3	607364	[[8]]	CLCNKB	602023	[[9]]
4A	1p36.13	[[10]]	Bartter syndrome, type 4, digenic	602522	[[11]]	CLCNKB	602023	[[9]]
	1p32.3	[[12]]	Bartter syndrome, type 4a			BSND	606412	[[13]]
	1p32.3	[[12]]	Sensorineural deafness with mild renal dysfunction			BSND	606412	[[13]]
4B	1p36.13	[[14]]	Bartter syndrome, type 4b, digenic	613090	[[15]]	CLCNKA	602024	[[16]]

病態

uptodate.1

循環血漿量軽度減少　→　RAA系亢進　→　二次性アルドステロン症
遠位尿細管へのナトリウムの到達　→　(接合尿細管や集合管でのナトリウムの再吸収と引き替えに)カリウム、水素イオン排泄の増加　→　代謝性アルカローシス、低カリウム血症(低カリウム血症によりさらに代謝アルカローシスが進む)。
低カリウム血症　→　尿濃縮力低下　→　腎性尿崩症

尿希釈能低下：ヘンレループ上行脚と遠位曲尿細管の療法は尿希釈に重要な部位であり(ADHの作用がない条件下で、水の移動なしにNaClを再吸収できるので)、本疾患では尿希釈能の低下をきたす。
尿濃縮能低下：尿濃縮にはループヘンレの正常な働きととADHが必要　→　本疾患では尿濃縮能の低下をきたす　⇔　ギテルマン症候群ではnot substantially impaired

症候および検査異常

uptodate.1

血圧低下　←　循環血漿量の減少、また腎からのプロスタグランジンE2(血管拡張)の放出増加が寄与。

しかし、出典不明の情報では、RAA系の亢進による血圧上昇がプロスタグランジンE2による血圧低下で相殺され、血圧正常とあるが、、、どうなの？出典はYNらしい。

発育遅滞、精神発達遅滞　　　←　　幼小児で発見されるきっかけ？
低カリウム血症
代謝性アルカローシス
多尿、多飲　←　尿濃縮能低下
尿中カルシウム：正常～増加
血清マグネシウム：正常～軽度低下
(時に)低リン酸血症　←　　二次性副甲状腺亢進症による

鑑別診断

IMD.1003

	カリウム	血圧	レニン	アルドステロン	pH	その他
Bartter症候群	低カリウム血症	正常	高値	高値	代謝性アルカローシス
原発性アルドステロン症	低カリウム血症	高血圧	低値	高値	代謝性アルカローシス
二次アルドステロン症	低カリウム血症	高血圧	高値	高値	代謝性アルカローシス
尿細管性アシドーシス	低カリウム血症				代謝性アシドーシス
甲状腺機能亢進症	低カリウム血症
Liddle症候群	低カリウム血症	高血圧	低値	低値		ACTH高値