K<sub>ir</sub>1.1 | Inwardly rectifying potassium channels | IUPHAR/BPS Guide to PHARMACOLOGY

Kir1.1

Target id: 429

Nomenclature: Kir1.1

Family: Inwardly rectifying potassium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for Kir1.1 in GtoImmuPdb

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 2 1 391 11q24 KCNJ1 potassium voltage-gated channel subfamily J member 1 18
Mouse 2 1 372 9 A4 Kcnj1 potassium inwardly-rectifying channel, subfamily J, member 1 14
Rat 2 1 391 8q21 Kcnj1 potassium voltage-gated channel subfamily J member 1 8
Previous and Unofficial Names
ROMK | ROMK1 | ROMK2 | ROMK3 | KAB-1 | ATP-regulated potassium channel ROM-K | ATP-sensitive inward rectifier potassium channel 1 | potassium channel, inwardly rectifying subfamily J, member 1 | potassium inwardly-rectifying channel
Database Links
CATH/Gene3D
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
NHERF-2 26
NHERF-1 26
CFTR 13
SUR2B 21
Functional Characteristics
Kir1.1 is weakly inwardly rectifying, as compared to classical (strong) inward rectifiers.
Ion Selectivity and Conductance
Species:  Rat
Rank order:  K+ [39.0 pS]
References:  8
Voltage Dependence Comments
Kir1.1 is a very weak inward rectifier, with essentially ohmic conduction at potentials below +60mV in symmetric K+ [8].
Ion Selectivity and Conductance (Rat)
NH4+ [62pS] > K+ [38. pS] > Tl+ [21pS] > Rb+ [15pS]  [4,8]

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
Extracellular K+ Rn Activation 2.3 pEC50 1x10-3 - 1x10-1 50.0 5
pEC50 2.3 Conc range: 1x10-3 - 1x10-1 M [5]
Holding voltage: 50.0 mV
Activator Comments
Increases in extracellular K+ counteract the Kir1.1 inactivation caused by intracellular acidification [5,17] and reduces block by cytoplasmic Mg2+ [25].
Gating inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
Intracellular H+ Rn Antagonist 6.8 pIC50 - -160.0 – -40.0 5,17,22
pIC50 6.8 [5,17,22]
Holding voltage: -160.0 – -40.0 mV
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
Ba2+ Hs Antagonist - - 1x10-3 -160.0 – 80.0 18
Conc range: 1x10-3 M [18]
Holding voltage: -160.0 – 80.0 mV
[125I]tertiapin Y1/K12/Q13 Rn Antagonist 9.2 pKd - Physiological 6
pKd 9.2 [6]
Holding voltage: Physiological
tertiapin-Q Rn Antagonist 8.2 – 8.9 pKi - Physiological/ -80.0 – 80.0 6,10
pKi 8.7 [10]
Holding voltage: -80.0 – 80.0 mV
pKi 8.2 – 8.9 [6,10]
Holding voltage: Physiological
VU591 Rn Inhibition 6.6 pKi 3x10-3 - 3x10-2 -120.0 – 20.0 1
pKi 6.6 (Ki 2.4x10-7 M) Conc range: 3x10-3 - 3x10-2 M [1]
Holding voltage: -120.0 – 20.0 mV
Cytoplasmic Mg2+ Rn - 2.3 pKi 2x10-4 - 5x10-3 0.0 16,25
pKi 2.3 (Ki 5x10-3 M) Conc range: 2x10-4 - 5x10-3 M [16,25]
Holding voltage: 0.0 mV
Extracellular Mg2+ Rn - 2.2 pKi 1x10-3 - 3x10-3 0.0 25
pKi 2.2 (Ki 6x10-3 M) Conc range: 1x10-3 - 3x10-3 M [25]
Holding voltage: 0.0 mV
tertiapin-Q Hs Inhibition 8.9 pIC50 - - 10
pIC50 8.9 [10]
Ba2+ Rn Antagonist 2.3 – 4.2 pIC50 1x10-4 0.0 – -100.0 8,27
pIC50 2.3 – 4.2 Conc range: 1x10-4 M [8,27]
Holding voltage: 0.0 – -100.0 mV
Cs+ Rn Antagonist 2.9 pIC50 - -120.0 27
pIC50 2.9 [27]
Holding voltage: -120.0 mV
View species-specific channel blocker tables
Channel Blocker Comments
Tertiapin does not effectively block human Kir1.1 channels [6]. Block by internal Mg2+, Ba2+ and Na+ depends on extracellular K+ [25]. Block by Ba2+, Mg2+ Cs+ and Na+ are voltage dependent [25].
Tissue Distribution
Kidney > skeletal muscle > pancreas > spleen > heart = brain > liver.
Species:  Human
Technique:  RT-PCR
References:  18
Kidney.
Species:  Human
Technique:  Northern Blot
References:  18
Kidney (outer medulla) > kidney (cortex), spleen, lung, eye, thalamus, hypothalamus.
Species:  Rat
Technique:  Northern Blot
References:  8
Kidney (cortical and medullary thick ascending limb, distal tubule, cortical and outer medullary collecting duct, inner medullary collecting duct).
Species:  Rat
Technique:  In situ hybridisation
References:  12
Kidney (apical membrane of cells in thick ascending limb, macula densa, distal convoluted tubule, connecting tubule, principle cells of cortical collecting duct).
Species:  Rat
Technique:  Immunohistochemistry
References:  15,23-24
Functional Assays
Voltage clamp recording of the cloned channel in a heterologous expression system.
Species:  Rat
Tissue:  Xenopus oocytes.
Response measured:  Current.
References:  8
Voltage clamp recording of the cloned channel in a heterologous expression system.
Species:  Rat
Tissue:  HEK 293 cells.
Response measured:  Current.
References:  6
Physiological Functions
K+ recycling in the thick ascending limb of loop of Henle, allowing NaCl uptake via Na-K-2Cl transporter.
Species:  None
Tissue:  Mammalian kidney
References:  7
K+ secretion by the principal cells of distal renal tubule.
Species:  None
Tissue:  Mammalian kidney
References:  7
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0009643 abnormal urine homeostasis PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0003031 acidosis PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0005528 decreased renal glomerular filtration rate PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0003653 decreased skin turgor PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0002843 decreased systemic arterial blood pressure PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0000519 hydronephrosis PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0005633 increased circulating sodium level PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0002608 increased hematocrit PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0001426 polydipsia PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0001762 polyuria PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0001732 postnatal growth retardation PMID: 12122007 
Kcnj1tm1Ges Kcnj1tm1Ges/Kcnj1tm1Ges
involves: 129X1/SvJ * Black Swiss
MGI:1927248  MP:0002082 postnatal lethality PMID: 12122007 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Bartter syndrome, antenatal, type 2
Synonyms: Antenatal Bartter syndrome [Orphanet: ORPHA93604]
Bartter disease [Disease Ontology: DOID:445]
Disease Ontology: DOID:445
OMIM: 241200
Orphanet: ORPHA93604
Role: 
References:  19
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Frameshift: Deletion Human 334fs36X 1557delAAAG 11
Frameshift: Deletion Human T313-K314X350 4-bp deletion 19
Frameshift: Insertion Human 13-14fs15 Insertion of a T-A base pair into a sequence of 6 consecutive T residues 19
Missense Human V72E 11
Missense Human D74Y 11
Missense Human W99C 11
Missense Human A103V 9
Missense Human D108H 11
Missense Human P110L 11
Missense Human V122E 11
Missense Human I142T 9
Missense Human G167E 11
Missense Human A195V 19
Missense Human A198T 11
Missense Human S200R 19
Missense Human S219R 20
Missense Human L220F 20
Missense Human V315G 11
Missense Human M338T 19
Nonsense Human W58X 19
Nonsense Human Y60X 19
Nonsense Human R338X 11
Nonsense Human 362X 9
Clinically-Relevant Mutations and Pathophysiology Comments
Locations are described relative to NP_722448.

In a genome-wide screen autosomal dominant migraine with aura has been found to link to a locus on 11q24. This region contains several candidate genes, including Kir1.1 and Kir3.4 [3].
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Amino acids:  391
Nucleotide accession: 
Protein accession: 
References:  18
Type:  Splice variant
Species:  Human
Amino acids:  372
Nucleotide accession: 
Protein accession: 
Type:  Splice variant
Species:  Rat
Amino acids:  372
Nucleotide accession: 
Protein accession: 
References:  2,28
Type:  Splice variant
Species:  Rat
Amino acids:  398
Nucleotide accession: 
References:  2
Biologically Significant Variant Comments
Six different splice variants have been identified (Kir1.1a-f) which produce 3 different protein products. The tissue distribution in the kidney varies for these splice variants [18]

References

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1. Bhave G, Chauder BA, Liu W, Dawson ES, Kadakia R, Nguyen TT, Lewis LM, Meiler J, Weaver CD, Satlin LM et al.. (2011) Development of a selective small-molecule inhibitor of Kir1.1, the renal outer medullary potassium channel. Mol. Pharmacol., 79 (1): 42-50. [PMID:20926757]

2. Boim MA, Ho K, Shuck ME, Bienkowski MJ, Block JH, Slightom JL, Yang Y, Brenner BM, Hebert SC. (1995) ROMK inwardly rectifying ATP-sensitive K+ channel. II. Cloning and distribution of alternative forms. Am. J. Physiol., 268 (6 Pt 2): F1132-40. [PMID:7611454]

3. Cader ZM, Noble-Topham S, Dyment DA, Cherny SS, Brown JD, Rice GP, Ebers GC. (2003) Significant linkage to migraine with aura on chromosome 11q24. Hum. Mol. Genet., 12 (19): 2511-7. [PMID:12915447]

4. Choe H, Sackin H, Palmer LG. (2000) Permeation properties of inward-rectifier potassium channels and their molecular determinants. J. Gen. Physiol., 115 (4): 391-404. [PMID:10736307]

5. Doi T, Fakler B, Schultz JH, Schulte U, Brändle U, Weidemann S, Zenner HP, Lang F, Ruppersberg JP. (1996) Extracellular K+ and intracellular pH allosterically regulate renal Kir1.1 channels. J. Biol. Chem., 271 (29): 17261-6. [PMID:8663367]

6. Felix JP, Liu J, Schmalhofer WA, Bailey T, Bednarek MA, Kinkel S, Weinglass AB, Kohler M, Kaczorowski GJ, Priest BT, Garcia ML. (2006) Characterization of Kir1.1 channels with the use of a radiolabeled derivative of tertiapin. Biochemistry, 45 (33): 10129-39. [PMID:16906771]

7. Giebisch G, Hebert SC, Wang WH. (2003) New aspects of renal potassium transport. Pflugers Arch., 446 (3): 289-97. [PMID:12684792]

8. Ho K, Nichols CG, Lederer WJ, Lytton J, Vassilev PM, Kanazirska MV, Hebert SC. (1993) Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature, 362 (6415): 31-8. [PMID:7680431]

9. Jeck N, Derst C, Wischmeyer E, Ott H, Weber S, Rudin C, Seyberth HW, Daut J, Karschin A, Konrad M. (2001) Functional heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney Int., 59 (5): 1803-11. [PMID:11318951]

10. Jin W, Lu Z. (1999) Synthesis of a stable form of tertiapin: a high-affinity inhibitor for inward-rectifier K+ channels. Biochemistry, 38 (43): 14286-93. [PMID:10572003]

11. Károlyi L, Konrad M, Köckerling A, Ziegler A, Zimmermann DK, Roth B, Wieg C, Grzeschik K-H, Koch MC, Seyberth HW. (1997) Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. International Collaborative Study Group for Bartter-like Syndromes. Hum. Mol. Genet., 6 (1): 17-26. [PMID:9002665]

12. Lee WS, Hebert SC. (1995) ROMK inwardly rectifying ATP-sensitive K+ channel. I. Expression in rat distal nephron segments. Am. J. Physiol., 268 (6 Pt 2): F1124-31. [PMID:7611453]

13. Lu M, Leng Q, Egan ME, Caplan MJ, Boulpaep EL, Giebisch GH, Hebert SC. (2006) CFTR is required for PKA-regulated ATP sensitivity of Kir1.1 potassium channels in mouse kidney. J. Clin. Invest., 116 (3): 797-807. [PMID:16470247]

14. Lu M, Wang T, Yan Q, Yang X, Dong K, Knepper MA, Wang W, Giebisch G, Shull GE, Hebert SC. (2002) Absence of small conductance K+ channel (SK) activity in apical membranes of thick ascending limb and cortical collecting duct in ROMK (Bartter's) knockout mice. J. Biol. Chem., 277 (40): 37881-7. [PMID:12130653]

15. Mennitt PA, Wade JB, Ecelbarger CA, Palmer LG, Frindt G. (1997) Localization of ROMK channels in the rat kidney. J. Am. Soc. Nephrol., 8 (12): 1823-30. [PMID:9402083]

16. Nichols CG, Ho K, Hebert S. (1994) Mg(2+)-dependent inward rectification of ROMK1 potassium channels expressed in Xenopus oocytes. J. Physiol. (Lond.), 476 (3): 399-409. [PMID:8057249]

17. Sackin H, Vasilyev A, Palmer LG, Krambis M. (2003) Permeant cations and blockers modulate pH gating of ROMK channels. Biophys. J., 84 (2 Pt 1): 910-21. [PMID:12547773]

18. Shuck ME, Bock JH, Benjamin CW, Tsai TD, Lee KS, Slightom JL, Bienkowski MJ. (1994) Cloning and characterization of multiple forms of the human kidney ROM-K potassium channel. J. Biol. Chem., 269 (39): 24261-70. [PMID:7929082]

19. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP. (1996) Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat. Genet., 14 (2): 152-6. [PMID:8841184]

20. Srivastava S, Li D, Edwards N, Hynes AM, Wood K, Al-Hamed M, Wroe AC, Reaich D, Moochhala SH, Welling PA et al.. (2013) Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter's syndrome and a functional analysis of their pathogenicity. Physiol Rep, 1 (6): e00160. [PMID:24400161]

21. Tanemoto M, Vanoye CG, Dong K, Welch R, Abe T, Hebert SC, Xu JZ. (2000) Rat homolog of sulfonylurea receptor 2B determines glibenclamide sensitivity of ROMK2 in Xenopus laevis oocyte. Am. J. Physiol. Renal Physiol., 278 (4): F659-66. [PMID:10751228]

22. Tsai TD, Shuck ME, Thompson DP, Bienkowski MJ, Lee KS. (1995) Intracellular H+ inhibits a cloned rat kidney outer medulla K+ channel expressed in Xenopus oocytes. Am. J. Physiol., 268 (5 Pt 1): C1173-8. [PMID:7762610]

23. Wade JB, Fang L, Coleman RA, Liu J, Grimm PR, Wang T, Welling PA. (2011) Differential regulation of ROMK (Kir1.1) in distal nephron segments by dietary potassium. Am. J. Physiol. Renal Physiol., 300 (6): F1385-93. [PMID:21454252]

24. Xu JZ, Hall AE, Peterson LN, Bienkowski MJ, Eessalu TE, Hebert SC. (1997) Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Am. J. Physiol., 273 (5 Pt 2): F739-48. [PMID:9374837]

25. Yang L, Frindt G, Palmer LG. (2010) Magnesium modulates ROMK channel-mediated potassium secretion. J. Am. Soc. Nephrol., 21 (12): 2109-16. [PMID:21030597]

26. Yoo D, Flagg TP, Olsen O, Raghuram V, Foskett JK, Welling PA. (2004) Assembly and trafficking of a multiprotein ROMK (Kir 1.1) channel complex by PDZ interactions. J. Biol. Chem., 279 (8): 6863-73. [PMID:14604981]

27. Zhou H, Chepilko S, Schütt W, Choe H, Palmer LG, Sackin H. (1996) Mutations in the pore region of ROMK enhance Ba2+ block. Am. J. Physiol., 271 (6 Pt 1): C1949-56. [PMID:8997197]

28. Zhou H, Tate SS, Palmer LG. (1994) Primary structure and functional properties of an epithelial K channel. Am. J. Physiol., 266 (3 Pt 1): C809-24. [PMID:8166245]

Contributors

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How to cite this page

Paul A. Slesinger, Colin G. Nichols, Lawrence G. Palmer, Henry Sackin, Stephen Tucker, John P. Adelman, David E. Clapham, Hiroshi Hibino, Atsushi Inanobe, Lily Y. Jan, Andreas Karschin, Yoshihiro Kubo, Yoshihisa Kurachi, Michel Lazdunski, Takashi Miki, Wade L. Pearson, Susumu Seino, Carol A. Vandenberg.
Inwardly rectifying potassium channels: Kir1.1. Last modified on 27/02/2018. Accessed on 17/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=429.