Article

Targeting of renal proximal tubule Na,K-ATPase by salt-inducible kinase

Department of Biochemistry, University at Buffalo, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 02/2010; 393(3):339-44. DOI: 10.1016/j.bbrc.2010.02.037
Source: PubMed

ABSTRACT The renal proximal tubule (RPT) is a central locale for Na+ reabsorption, and blood pressure regulation. Na+ reabsorption in the RPT depends upon the Na,K-ATPase, which is controlled by a complex regulatory network, including Salt-Inducible Protein Kinase (SIK). SIKs are recently discovered members of the AMP-activated Protein Kinase (AMPK) family, which regulate salt homeostasis and metabolism in a number of tissues. In the RPT, SIK interacts with the Na,K-ATPase in the basolateral membrane (BM), regulating both the activity and level of Na,K-ATPase in the BM. Thus, Na,K-ATPase activity can be rapidly adjusted in response to changes in Na+ balance. Long-term changes in Na+ intake affect the state of SIK phosphorylation, and as a consequence the phosphorylation of TORCs, Transducers of Regulated CREB (cAMP Regulatory Element Binding Protein). Once phosphorylated, TORCs enter the nucleus, and activate transcription of the ATP1B1 gene encoding for the Na,K-ATPase beta subunit.

Download full-text

Full-text

Available from: Mary Taub, Jun 26, 2015
0 Followers
 · 
86 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The inward rectifier K(+) channel Kir2.1 participates in the maintenance of the cell membrane potential in a variety of cells including neurons and cardiac myocytes. Mutations of KCNJ2 encoding Kir2.1 underlie the Andersen-Tawil syndrome, a rare disorder clinically characterized by periodic paralysis, cardiac arrhythmia and skeletal abnormalities. The maintenance of the cardiac cell membrane potential is decreased in ischaemia, which is known to stimulate the AMP-activated serine/threonine protein kinase (AMPK). This energy-sensing kinase stimulates energy production and limits energy utilization. The present study explored whether AMPK regulates Kir2.1. To this end, cRNA encoding Kir2.1 was injected into Xenopus oocytes with and without additional injection of wild type AMPK (AMPKα1+AMPKβ1+AMPKγ1), of the constitutively active (γR70Q)AMPK (α1β1γ1(R70Q)), of the kinase dead mutant (αK45R)AMPK (α1(K45R)β1γ1), or of the ubiquitin ligase Nedd4-2. Kir2.1 activity was determined in two-electrode voltage-clamp experiments. Moreover, Kir2.1 protein abundance in the cell membrane was determined by immunostaining and subsequent confocal imaging. As a result, wild type and constitutively active AMPK significantly reduced Kir2.1-mediated currents and Kir2.1 protein abundance in the cell membrane. Expression of wild type Nedd4-2 or of Nedd4-2(S795A) lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2(S795A) was significantly augmented by additional coexpression of AMPK. In conclusion, AMPK is a potent regulator of Kir2.1. AMPK is at least partially effective through phosphorylation of the ubiquitin ligase Nedd4-2.
    Biochemical and Biophysical Research Communications 05/2011; 408(4):505-10. DOI:10.1016/j.bbrc.2011.04.015 · 2.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To locate components and target proteins of relevance for the cAMP and cGMP signaling networks including cAMP and cGMP phosphodiesterases (PDEs), salt-inducible kinases (SIKs), subunits of Na+, K+-ATPases, and aquaporins (AQPs) in the human saccule. Methods: The human saccule was dissected out during the removal of vestibular schwannoma via the translabyrinthine approach and immediately fixed. Immunohistochemistry was performed using PDE, SIK, Na(+), K(+)-ATPase, and AQP antibodies. Results: PDEs selective for cAMP (PDE4A, PDE4D, and PDE8A) and cGMP (PDE9A) as well a dual specificity PDE (PDE10A) were detected in the sensory epithelium of the saccule. Furthermore, AQP2, 4, and 9, SIK1 and the α-1 subunit of the Na(+), K(+)-ATPase were detected. Conclusion: cAMP and cGMP are important regulators of ion and water homeostasis in the inner ear. The identification of PDEs and SIK1 in the vestibular system offers new treatment targets for endolymphatic hydrops. Exactly how the PDEs are connected to SIK1 and the SIK1 substrate Na(+), K(+)-ATPase and to AQPs 2, 4, 9 remains to be elucidated. The dissection of the signaling networks utilizing these components and evaluating their roles will add new basic knowledge regarding inner ear physiology.
    Frontiers in Neurology 08/2011; 2:48. DOI:10.3389/fneur.2011.00048
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Na+,K+-ATPase, or sodium pump, is well known for its role in ion transport across the plasma membrane of animal cells. It carries out the transport of Na+ ions out of the cell and of K+ ions into the cell and thus maintains electrolyte and fluid balance. In addition to the fundamental ion-pumping function of the Na+,K+-ATPase, recent work has suggested additional roles for Na+,K+-ATPase in signal transduction and biomembrane structure. Several signaling pathways have been found to involve Na+,K+-ATPase, which serves as a docking station for a fast-growing number of protein interaction partners. In this review, we focus on Na+,K+-ATPase as a signal transducer, but also briefly discuss other Na+,K+-ATPase protein–protein interactions, providing a comprehensive overview of the diverse signaling functions ascribed to this well-known enzyme.
    Cellular and Molecular Life Sciences CMLS 01/2012; 70(2). DOI:10.1007/s00018-012-1039-9 · 5.86 Impact Factor