User:Paracoccidioidomycosis/Na–K–Cl cotransporter
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Article Draft
[edit]Lead
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Generally, this is a very well-studied transporter, especially the NKCC2 isoform, for its therapeutic potential in renal physiology. Although the sections in this article seem to be already fleshed out, there is a wealth of information that has yet to be added. This, my goal would be to expand on almost all the sections here.
I created a figure to the right that I would like to add to the page. It is a simple drawing of how the NKCC cotransporter works, regardless of the species or isoform.
For Paragraph 2: In contrast, NKCC2 is found specifically in the kidney, where it extracts sodium, potassium, and chloride from the urine so they can be reabsorbed into the blood[1].
Article body
[edit]Function
[edit]For paragraph 1: The rate of transport of these ions are regulated by phosphorylation sites, which present on both NKCC isoforms[2].
NKCC1
[edit]New paragraph: The NKCC1 isoform consists of about 1,200 amino acids, with about 500 amino acids residues giving rise to twelve hydrophobic transmembrane regions[3]. However, evidence of a shorter NKCC1 mRNA transcript (6.7 kb to 7-7.5 kb) in skeletal muscle cells gives support that further NKCC1 variants exists in a tissue-specific manner[4]. The carboxy-terminal of the NKCC1 cotransporter contains multiple phosphorylation sites and is highly conserved across species, while in contrast, the amino-terminal contains at least one phosphorylation site and is poorly conserved across species[3].Focusing on the transmembrane regions, mutagenesis-driven affinity studies have revealed the second transmembrane region as the determinant of cation affinity, while chloride affinity was determined by transmembrane regions four through seven[3]. Additionally, bumetanide, a loop diuretic, was found to bind to transmembrane regions 2 through 7, 11, and 12[3].
For paragraph 1: Exon 21 possesses a translocation sequence that targets NKCC1 to the basolateral membrane[5]. Thus, NKCC1 cotransporters that have been alternatively spliced to exclude exon 21 will be translocated to the apical membrane rather than the basolateral membrane.
For paragraph 2: Specifically in the cochlea, NKCC1 is present in the stria vascularis, spiral ligament, and spiral ganglia[6]. Similarly, NKCC1 expression decreases with aging, resulting in progressive hearing loss[7]. Additionally, NKCC1 is present in the dark cells of the vestibule and contributes to generation of the endolymph of the vestibular system[8].
New paragraph: NKCC1 has been identified in Sertoli cells, spermatocytes, and spermatids in the male reproductive system[9]. NKCC1 function appears to be critical for spermatogenesis, as knockdown of NKCC1 in mice results in spermatocytes failing to mature into spermatozoa, resulting in infertility[9]. Additionally, the NKCC1 knockdown mice also exhibit a decreased testicle size compared to wild-type mice[9]. The mechanism behind NKCC1-dependent male fertility is unclear, it is possible that the observed decreased sperm count could be due to either lack of NKCC1 cotransport in the testis or upstream failure of NKCC1-expressing neurons in the hypothalamus to release gonadotropin-releasing hormone[2].
NKCC2
[edit]New paragraph: The NKCC2 isoform is smaller than NKCC1, 121 kDa versus 195 kDa, respectively, primarily because NKCC2 does not contain an 80 amino acid sequence present on the N-terminus of NKCC1[1]. Additionally, the NKCC2 isoform does not contain exon 21, which results in NKCC2 being translocated to the apical membrane[2]. Compared to NKCC1, exon 1 is divided into two separate exons in NKCC2 and exon 4 is alternatively spliced into forms A, B, and F, which are all exclusive to NKCC2[2]. NKCC2 expression is thought to be limited to renal cells, although this has been called into question with possible NKCC2 expression in pancreatic β-cells[10].
Genetics
[edit]New paragraph: The promotor for gene SLC12A2, which encodes for NKCC1, contains binding sites for homeobox transcription factors SIX1 and SIX4, which have been shown to upregulate NKCC1 mRNA expression when bound[11]. Additionally, NKCC1 expression is upregulated when the SLC12A2 promoter is hypomethylated due to transcription factor Sp1 binding[12].
New paragraph: Unlike SLC12A2, the promotor for gene SLC12A1, which encodes for NKCC2, does not contain either a TATA box or Sp1 binding sites[2]. Regulatory binding sites in the NKCC2 promotor include sites for hepatocyte nuclear factor 1, cAMP-response element binding protein, CCAAT-enhancer binding proteins, and basic helix-loop-helix proteins[2].
References
[edit]Review: Sodium-potassium-chloride cotransport. https://pubmed.ncbi.nlm.nih.gov/10617769/
Review: Na+ -K+ -2Cl- Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia. https://pubmed.ncbi.nlm.nih.gov/29687903/
Primary article: NKCC transport mediates the insulinotropic effects of taurine and other small neutral amino acids. https://pubmed.ncbi.nlm.nih.gov/36669678/
Primary article: The opposing chloride cotransporters KCC and NKCC control locomotor activity in constant light and during long days. https://pubmed.ncbi.nlm.nih.gov/35303416/
- ^ a b Russell, John M. (2000-01-01). "Sodium-Potassium-Chloride Cotransport". Physiological Reviews. 80 (1): 211–276. doi:10.1152/physrev.2000.80.1.211. ISSN 0031-9333.
- ^ a b c d e f Terjung, Ronald, ed. (2011-01-17). Comprehensive Physiology (1 ed.). Wiley. doi:10.1002/cphy.c170018. ISBN 978-0-470-65071-4.
- ^ a b c d Payne, John A; Forbush, Bliss (1995-01-01). "Molecular characterization of the epithelial NaKCl cotransporter isoforms". Current Opinion in Cell Biology. 7 (4): 493–503. doi:10.1016/0955-0674(95)80005-0. ISSN 0955-0674.
- ^ Payne, John A.; Xu, Jian-Chao; Haas, Melanie; Lytle, Christian Y.; Ward, David; Forbush, Bliss (1995-07). "Primary Structure, Functional Expression, and Chromosomal Localization of the Bumetanide-sensitive Na-K-Cl Cotransporter in Human Colon". Journal of Biological Chemistry. 270 (30): 17977–17985. doi:10.1074/jbc.270.30.17977. ISSN 0021-9258.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: unflagged free DOI (link) - ^ Carmosino, Monica; Giménez, Ignacio; Caplan, Michael; Forbush, Biff (2008-10). Mostov, Keith E. (ed.). "Exon Loss Accounts for Differential Sorting of Na-K-Cl Cotransporters in Polarized Epithelial Cells". Molecular Biology of the Cell. 19 (10): 4341–4351. doi:10.1091/mbc.e08-05-0478. ISSN 1059-1524. PMC 2555935. PMID 18667527.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: PMC format (link) - ^ Delpire, Eric; Lu, Jianming; England, Roger; Dull, Christopher; Thorne, Tina (1999-06). "Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter". Nature Genetics. 22 (2): 192–195. doi:10.1038/9713. ISSN 1061-4036.
{{cite journal}}: Check date values in:|date=(help) - ^ Diaz, Rodney C.; Vazquez, Ana Elena; Dou, Hongwei; Wei, Dongguang; Cardell, Emma Lou; Lingrel, Jerry; Shull, Gary E.; Doyle, Karen Jo; Yamoah, Ebenezer N. (2007-11-02). "Conservation of Hearing by Simultaneous Mutation of Na,K-ATPase and NKCC1". Journal of the Association for Research in Otolaryngology. 8 (4): 422–434. doi:10.1007/s10162-007-0089-4. ISSN 1525-3961. PMC 2538340. PMID 17674100.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Ciuman, R R (2009-02). "Stria vascularis and vestibular dark cells: characterisation of main structures responsible for inner-ear homeostasis, and their pathophysiological relations". The Journal of Laryngology & Otology. 123 (2): 151–162. doi:10.1017/S0022215108002624. ISSN 0022-2151.
{{cite journal}}: Check date values in:|date=(help) - ^ a b c Pace, Amy J.; Lee, Eddie; Athirakul, Krairek; Coffman, Thomas M.; O’Brien, Deborah A.; Koller, Beverly H. (2000-02-15). "Failure of spermatogenesis in mouse lines deficient in the Na+-K+-2Cl– cotransporter". Journal of Clinical Investigation. 105 (4): 441–450. doi:10.1172/JCI8553. ISSN 0021-9738. PMC 289162. PMID 10683373.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Alshahrani, Saeed; Almutairi, Mohammed Mashari; Kursan, Shams; Dias-Junior, Eduardo; Almiahuob, Mohamed Mahmoud; Aguilar-Bryan, Lydia; Di Fulvio, Mauricio (2015-12). "Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice". Journal of Endocrinology. 227 (3): 153–165. doi:10.1530/JOE-15-0327. ISSN 0022-0795. PMC 4623298. PMID 26400961.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: PMC format (link) - ^ Ando, Zen‐ichi; Sato, Shigeru; Ikeda, Keiko; Kawakami, Kiyoshi (2005-06). "Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4". The FEBS Journal. 272 (12): 3026–3041. doi:10.1111/j.1742-4658.2005.04716.x. ISSN 1742-464X.
{{cite journal}}: Check date values in:|date=(help) - ^ Cho, Hyun-Min; Lee, Hae-Ahm; Kim, Hye Young; Lee, Dong-Youb; Kim, In Kyeom (2013-07). "Recruitment of Specificity Protein 1 by CpG hypomethylation upregulates Na+-K+-2Cl− cotransporter 1 in hypertensive rats". Journal of Hypertension. 31 (7): 1406–1413. doi:10.1097/HJH.0b013e3283610fed. ISSN 0263-6352.
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