ArticleHuman molecular genetics2015
Critical role of the SPAK protein kinase CCT domain in controlling blood pressure.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 24 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 40 citations in OpenAlex.
- Exploring the Role of the SLC12A Cation-Coupled Chloride Cotransporters in the Cardiovascular System.Cells · 2026Review
- Kinase interaction analysis predicts actions of the WNK-OSR1/SPAK pathway.Communications biology · 2025Article
- NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress.Science advances · 2025Article
- Arginine vasopressin regulates the renal NaAmerican journal of physiology. Renal physiology · 2024Article
- The role ofJournal of pharmaceutical analysis · 2023Review
- CCT and CCT-Like Modular Protein Interaction Domains in WNK Signaling.Molecular pharmacology · 2022Review
- Role of the cation-chloride-cotransporters in the circadian system.Asian journal of pharmaceutical sciences · 2021Review
- Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension.Acta pharmaceutica Sinica. B · 2021Review
- WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension.Acta pharmacologica Sinica · 2021Review
- Molecular characteristics and physiological roles of NaJournal of cellular physiology · 2021Review
- Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke.International journal of molecular sciences · 2021Review
- Review
- Modulation of brain cation-ClNature communications · 2020Article
- Physiological Processes Modulated by the Chloride-Sensitive WNK-SPAK/OSR1 Kinase Signaling Pathway and the Cation-Coupled Chloride Cotransporters.Frontiers in physiology · 2020Review
- The Molecular Genetics of Gordon Syndrome.Genes · 2019Review
- Emerging Targets of Diuretic Therapy.Clinical pharmacology and therapeutics · 2017Review
- Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport.Expert opinion on therapeutic targets · 2017Review
- Gender difference in kidney electrolyte transport. I. Role of ATAmerican journal of physiology. Renal physiology · 2017Article
- WNK signalling pathways in blood pressure regulation.Cellular and molecular life sciences : CMLS · 2017Review
- Functional kinomics establishes a critical node of volume-sensitive cation-ClScientific reports · 2016Article
Corrections and comments
- Erratum issued
Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
The STE20/SPS1-related proline/alanine-rich kinase (SPAK) controls blood pressure (BP) by phosphorylating and stimulating the Na-Cl (NCC) and Na-K-2Cl (NKCC2) co-transporters, which regulate salt reabsorption in the kidney. SPAK possesses a conserved carboxy-terminal (CCT) domain, which recognises RFXV/I motifs present in its upstream activator [isoforms of the With-No-lysine (K) kinases (WNKs)] as well as its substrates (NCC and NKCC2). To define the physiological importance of the CCT domain, we generated knock-in mice in which the critical CCT domain Leu502 residue required for high affinity recognition of the RFXI/V motif was mutated to Alanine. The SPAK CCT domain defective knock-in animals are viable, and the Leu502Ala mutation abolished co-immunoprecipitation of SPAK with WNK1, NCC and NKCC2. The CCT domain defective animals displayed markedly reduced SPAK activity and phosphorylation of NCC and NKCC2 co-transporters at the residues phosphorylated by SPAK. This was also accompanied by a reduction in the expression of NCC and NKCC2 protein without changes in mRNA levels. The SPAK CCT domain knock-in mice showed typical features of Gitelman Syndrome with mild hypokalaemia, hypomagnesaemia, hypocalciuria and displayed salt wasting on switching to a low-Na diet. These observations establish that the CCT domain plays a crucial role in controlling SPAK activity and BP. Our results indicate that CCT domain inhibitors would be effective at reducing BP by lowering phosphorylation as well as expression of NCC and NKCC2.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.