ArticleProceedings of the National Academy of Sciences of the United States of America2011
Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 105 citations in OpenAlex.
- KCNJ16 tubulopathy presenting with recurrent acute flaccid paralysis and sensorineural hearing loss.Pediatric nephrology (Berlin, Germany) · 2026Article
- Stimulation of basolateral calcium-sensing receptor inhibits Kir4.1/Kir5.1 in the mouse distal convoluted tubule.American journal of physiology. Renal physiology · 2026Article
- Kir5.1 regulates Kir4.2 expression and is a key component of the 50-pS inwardly rectifying potassium channel in basolateral membrane of mouse proximal tubules.American journal of physiology. Renal physiology · 2025Article
- Role of KThe American journal of pathology · 2025Article
- mTORc2 in Distal Convoluted Tubule and Renal K + Excretion during High Dietary K + Intake.Journal of the American Society of Nephrology : JASN · 2024Article
- Role of calcineurin in regulating renal potassium (KActa physiologica (Oxford, England) · 2024Review
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Calcineurin inhibitors stimulate Kir4.1/Kir5.1 of the distal convoluted tubule to increase NaCl cotransporter.JCI insight · 2023Article
- Diverse functions of the inward-rectifying potassium channel Kir5.1 and its relationship with human diseases.Frontiers in physiology · 2023Review
- Multiple molecular mechanisms are involved in the activation of the kidney sodium-chloride cotransporter by hypokalemia.Kidney international · 2022Article
- Kir5.1 channels: potential role in epilepsy and seizure disorders.American journal of physiology. Cell physiology · 2022Review
- Inwardly rectifying KAmerican journal of physiology. Cell physiology · 2022Review
- Crosstalk between epithelial sodium channels (ENaC) and basolateral potassium channels (KBritish journal of pharmacology · 2022Article
- Inwardly rectifying potassium channels mediate polymyxin-induced nephrotoxicity.Cellular and molecular life sciences : CMLS · 2022Article
- Molecular mechanisms for the modulation of blood pressure and potassium homeostasis by the distal convoluted tubule.EMBO molecular medicine · 2022Review
- Editorial: Insights in renal and epithelial physiology: 2021.Frontiers in physiology · 2022Article
- EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies.Frontiers in physiology · 2022Review
- Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology.American journal of physiology. Cell physiology · 2021Review
- Deletion of Kir5.1 abolishes the effect of high NaAmerican journal of physiology. Renal physiology · 2021Article
- Inwardly rectifying potassium channel 5.1: Structure, function, and possible roles in diseases.Genes & diseases · 2021Review
4 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The heteromeric inwardly rectifying Kir4.1/Kir5.1 K(+) channel underlies the basolateral K(+) conductance in the distal nephron and is extremely sensitive to inhibition by intracellular pH. The functional importance of Kir4.1/Kir5.1 in renal ion transport has recently been highlighted by mutations in the human Kir4.1 gene (KCNJ10) that result in seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME)/epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) syndrome, a complex disorder that includes salt wasting and hypokalemic alkalosis. Here, we investigated the role of the Kir5.1 subunit in mice with a targeted disruption of the Kir5.1 gene (Kcnj16). The Kir5.1(-/-) mice displayed hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria. The short-term responses to hydrochlorothiazide, an inhibitor of ion transport in the distal convoluted tubule (DCT), were also exaggerated, indicating excessive renal Na(+) absorption in this segment. Furthermore, chronic treatment with hydrochlorothiazide normalized urinary excretion of Na(+) and Ca(2+), and abolished acidosis in Kir5.1(-/-) mice. Finally, in contrast to WT mice, electrophysiological recording of K(+) channels in the DCT basolateral membrane of Kir5.1(-/-) mice revealed that, even though Kir5.1 is absent, there is an increased K(+) conductance caused by the decreased pH sensitivity of the remaining homomeric Kir4.1 channels. In conclusion, disruption of Kcnj16 induces a severe renal phenotype that, apart from hypokalemia, is the opposite of the phenotype seen in SeSAME/EAST syndrome. These results highlight the important role that Kir5.1 plays as a pH-sensitive regulator of salt transport in the DCT, and the implication of these results for the correct genetic diagnosis of renal tubulopathies is discussed.
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