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Contents:
- Gene and Protein Information
- Previous and Unofficial Names
- Database Links
- Associated Proteins
- Functional Characteristics
- Ion Selectivity and Conductance
- Voltage Dependence
- Rank order lists
- Activators
- Gating Inhibitors
- Channel Blockers
- Tissue Distribution
- Functional Assays
- Physiological Functions
- Phenotypes, Alleles and Disease Models
- Clinically-Relevant Mutations and Pathophysiology
- Biologically Significant Variants
- General Comments
- References
- Contributors
- How to cite this page
Gene and Protein Information  |
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| Species | TM | P Loops | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 2 | 1 | 391 | 11q24.3 | KCNJ1 | potassium inwardly rectifying channel subfamily J member 1 | 23 |
| Mouse | 2 | 1 | 372 | 9 A4 | Kcnj1 | potassium inwardly-rectifying channel, subfamily J, member 1 | 19 |
| Rat | 2 | 1 | 391 | 8q21 | Kcnj1 | potassium inwardly-rectifying channel, subfamily J, member 1 | 12 |
| Previous and Unofficial Names |
| potassium inwardly rectifying channel subfamily J member 1 | ATP-regulated potassium channel ROM-K | ATP-sensitive inward rectifier potassium channel 1 | KAB-1 | potassium channel, inwardly rectifying subfamily J, member 1 | potassium inwardly-rectifying channel | potassium voltage-gated channel subfamily J member 1 | ROMK | ROMK1 | ROMK2 | ROMK3 |
| Database Links |
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| Alphafold | P48048 (Hs), O88335 (Mm), P35560 (Rn) |
| CATH/Gene3D | 2.60.40.1400 |
| ChEMBL Target | CHEMBL1293292 (Hs), CHEMBL2146350 (Rn) |
| DrugBank Target | P48048 (Hs) |
| Ensembl Gene | ENSG00000151704 (Hs), ENSMUSG00000041248 (Mm), ENSRNOG00000059005 (Rn) |
| Entrez Gene | 3758 (Hs), 56379 (Mm), 24521 (Rn) |
| Human Protein Atlas | ENSG00000151704 (Hs) |
| KEGG Gene | hsa:3758 (Hs), mmu:56379 (Mm), rno:24521 (Rn) |
| OMIM | 600359 (Hs) |
| Orphanet | ORPHA122783 (Hs) |
| Pharos | P48048 (Hs) |
| RefSeq Nucleotide | NM_153764 (Hs), NM_000220 (Hs), NM_019659 (Mm), AF081367 (Rn), NM_017023 (Rn), L29403 (Rn) |
| RefSeq Protein | NP_722448 (Hs), NP_000211 (Hs), NP_062633 (Mm), NP_058719 (Rn) |
| UniProtKB | P48048 (Hs), O88335 (Mm), P35560 (Rn) |
| Wikipedia | KCNJ1 (Hs) |
| Associated Proteins |
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| Functional Characteristics |
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| Kir1.1 is weakly inwardly rectifying, as compared to classical (strong) inward rectifiers. | |
| Ion Selectivity and Conductance |
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| Voltage Dependence Comments |
| Kir1.1 is a very weak inward rectifier, with essentially ohmic conduction at potentials below +60mV in symmetric K+ [12]. |
| Ion Selectivity and Conductance (Rat) |
| NH4+ [62pS] > K+ [38. pS] > Tl+ [21pS] > Rb+ [15pS] [5,12] |
Download all structure-activity data for this target as a CSV file 
| Activators | ||||||||||||||||||||||||
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| Activator Comments | ||||||||||||||||||||||||
| Increases in extracellular K+ counteract the Kir1.1 inactivation caused by intracellular acidification [6,22] and reduces block by cytoplasmic Mg2+ [31]. | ||||||||||||||||||||||||
| Gating inhibitors
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| Channel Blockers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific channel blocker tables | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Channel Blocker Comments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tertiapin does not effectively block human Kir1.1 channels [7]. Block by internal Mg2+, Ba2+ and Na+ depends on extracellular K+ [31]. Block by Ba2+, Mg2+ Cs+ and Na+ are voltage dependent [31]. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tissue Distribution
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| Functional Assays
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| Physiological Functions
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| 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 [4]. |
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| Biologically Significant Variants
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| 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 [23] |
| General Comments |
| Kir1.1 (renal outer medullary potassium (ROMK) channel) is a molecular target for novel diuretics for the treatment of hypertension and heart failure [8]. The working hypothesis being that inhibition of Kir1.1 channels in the kidney, by novel small molecules, would yield the diuretic/natriuretic efficacy of existing diuretic drugs, but would have reduced potential for unwanted side effects such as dose-limiting hypokalemia [9]. A review of the medicinal chemistry effort that has been dedicated to the development of Kir1.1 channel blockers/inhibitors with therapeutic potential was published by Aretz et al. in 2019 [1]. The first small molecule Kir1.1 clinical candidate was the Merck compound MK-7145 [11,27]. However, clinical progress appears to have stalled, with one study (NCT01558674) stating 'Lack of efficacy' as the reason for termination. |
References
1. Aretz CD, Vadukoot AK, Hopkins CR. (2019) Discovery of Small Molecule Renal Outer Medullary Potassium (ROMK) Channel Inhibitors: A Brief History of Medicinal Chemistry Approaches To Develop Novel Diuretic Therapeutics. J Med Chem, 62 (19): 8682-8694. [PMID:31034224]
2. 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]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. Garcia ML, Kaczorowski GJ. (2014) Targeting the inward-rectifier potassium channel ROMK in cardiovascular disease. Curr Opin Pharmacol, 15: 1-6. [PMID:24721647]
9. Garcia ML, Priest BT, Alonso-Galicia M, Zhou X, Felix JP, Brochu RM, Bailey T, Thomas-Fowlkes B, Liu J, Swensen A et al.. (2014) Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis. J Pharmacol Exp Ther, 348 (1): 153-64. [PMID:24142912]
10. Giebisch G, Hebert SC, Wang WH. (2003) New aspects of renal potassium transport. Pflugers Arch, 446 (3): 289-97. [PMID:12684792]
11. Hampton C, Zhou X, Priest BT, Pai LY, Felix JP, Thomas-Fowlkes B, Liu J, Kohler M, Xiao J, Corona A et al.. (2016) The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype. J Pharmacol Exp Ther, 359 (1): 194-206. [PMID:27432892]
12. 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]
13. 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]
14. Jiang J, Ding FX, Zhou X, Bateman TJ, Dong S, Gu X, Keh deJesus R, Pio B, Tang H, Chobanian HR et al.. (2021) Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic. J Med Chem, 64 (11): 7691-7701. [PMID:34038119]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. 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]
22. 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]
23. 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]
24. 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]
25. 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]
26. 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]
27. Tang H, Zhu Y, Teumelsan N, Walsh SP, Shahripour A, Priest BT, Swensen AM, Felix JP, Brochu RM, Bailey T et al.. (2016) Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure. ACS Med Chem Lett, 7 (7): 697-701. [PMID:27437080]
28. 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]
29. 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]
30. 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]
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32. 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]
33. 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]
34. 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]
How to cite this page
Adelman JP, Clapham DE, Hibino H, Inanobe A, Jan LY, Karschin A, Kubo Y, Kurachi Y, Lazdunski M, Miki T, Nichols CG, Palmer LG, Pearson WL, Sackin H, Seino S, Slesinger PA, Tucker S, Vandenberg CA. Inwardly rectifying potassium channels (KIR) in GtoPdb v.2023.1. IUPHAR/BPS Guide to Pharmacology CITE. 2023; 2023(1). Available from: https://doi.org/10.2218/gtopdb/F74/2023.1.
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