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2.A.30.1.2
Solute carrier family 12 member 1 (Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2) (Kidney-specific Na-K-Cl symporter, NKCC2) Mutations cause type I Bartter syndrome (BS), a life threatening kidney disease featuring arterial hypotension along with electrolyte abnormalities (Adachi et al. 2007).  An OS9-mediated ERAD pathway in renal cells degrades immature NKCC2 proteins (Seaayfan et al. 2015). It is regulated by AMPK (see 8.A.104.1.1). The WNK kinase-dependent pathway can affect both the trafficking and the intrinsic activity of NKCC2, which therefore plays a doubly important role in carrier regulation (Marcoux et al. 2019). The gene encodes three splice variants. They are identical to each other except for TMS2 and the following connecting segment (CS2). These variants do not share the same localization, transport characteristics and physiological roles along the thick assending loop of Henle (Marcoux et al. 2019).  NKCC2 regulation in the thick ascending limb has been updated and involves membrane trafficking, phosphorylation, and protein-protein interactions (Maskey et al. 2024).

Accession Number:Q13621
Protein Name:Solute carrier family 12 member 1
Length:1099
Molecular Weight:121450.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate sodium chloride, potassium chloride

Cross database links:

Entrez Gene ID: 6557   
Pfam: PF00324    PF08403   
KEGG: hsa:6557   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005624 C:membrane fraction
GO:0005886 C:plasma membrane
GO:0008511 F:sodium:potassium:chloride symporter activity
GO:0006813 P:potassium ion transport
GO:0006814 P:sodium ion transport

References (3)

[1] “Bartter's syndrome, hypokalemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.”  Simon D.B.et.al.   8640224
[2] “Analysis of the DNA sequence and duplication history of human chromosome 15.”  Zody M.C.et.al.   16572171
[3] “Similar Effects of all WNK3 Variants upon SLC12 Cotransporters.”  Cruz-Rangel S.et.al.   21613606

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence 
1:	MSLNNSSNVF LDSVPSNTNR FQVSVINENH ESSAAADDNT DPPHYEETSF GDEAQKRLRI 
61:	SFRPGNQECY DNFLQSGETA KTDASFHAYD SHTNTYYLQT FGHNTMDAVP KIEYYRNTGS 
121:	ISGPKVNRPS LLEIHEQLAK NVAVTPSSAD RVANGDGIPG DEQAENKEDD QAGVVKFGWV 
181:	KGVLVRCMLN IWGVMLFIRL SWIVGEAGIG LGVLIILLST MVTSITGLST SAIATNGFVR 
241:	GGGAYYLISR SLGPEFGGSI GLIFAFANAV AVAMYVVGFA ETVVDLLKES DSMMVDPTND 
301:	IRIIGSITVV ILLGISVAGM EWEAKAQVIL LVILLIAIAN FFIGTVIPSN NEKKSRGFFN 
361:	YQASIFAENF GPRFTKGEGF FSVFAIFFPA ATGILAGANI SGDLEDPQDA IPRGTMLAIF 
421:	ITTVAYLGVA ICVGACVVRD ATGNMNDTII SGMNCNGSAA CGLGYDFSRC RHEPCQYGLM 
481:	NNFQVMSMVS GFGPLITAGI FSATLSSALA SLVSAPKVFQ ALCKDNIYKA LQFFAKGYGK 
541:	NNEPLRGYIL TFLIAMAFIL IAELNTIAPI ISNFFLASYA LINFSCFHAS YAKSPGWRPA 
601:	YGIYNMWVSL FGAVLCCAVM FVINWWAAVI TYVIEFFLYV YVTCKKPDVN WGSSTQALSY 
661:	VSALDNALEL TTVEDHVKNF RPQCIVLTGG PMTRPALLDI THAFTKNSGL CICCEVFVGP 
721:	RKLCVKEMNS GMAKKQAWLI KNKIKAFYAA VAADCFRDGV RSLLQASGLG RMKPNTLVIG 
781:	YKKNWRKAPL TEIENYVGII HDAFDFEIGV VIVRISQGFD ISQVLQVQEE LERLEQERLA 
841:	LEATIKDNEC EEESGGIRGL FKKAGKLNIT KTTPKKDGSI NTSQSMHVGE FNQKLVEAST 
901:	QFKKKQEKGT IDVWWLFDDG GLTLLIPYIL TLRKKWKDCK LRIYVGGKIN RIEEEKIVMA 
961:	SLLSKFRIKF ADIHIIGDIN IRPNKESWKV FEEMIEPYRL HESCKDLTTA EKLKRETPWK 
1021:	ITDAELEAVK EKSYRQVRLN ELLQEHSRAA NLIVLSLPVA RKGSISDLLY MAWLEILTKN 
1081:	LPPVLLVRGN HKNVLTFYS