Cellular/molecular Na,K-ATPase regulation in choroid plexus

Summary

Principal Investigator: KATHLEEN SWEADNER
Affiliation: Harvard University
Country: USA
Abstract: DESCRIPTION (provided by applicant): One long term objective is to understand the biochemical and cellular mechanisms of the regulation of the sodium pump (Na,K-ATPase), which is the driving force for cerebrospinal fluid (CSF) secretion. The other is to understand how that regulation is coordinated with the unique morphological changes in the secretory epithelium. We have data that indicate that phosphorylation events at the apical membrane coordinate the regulation of Na,K-ATPase with the regulation of secretory cell morphology. CSF is produced by the choroid plexuses in the brain's ventricles, and it flows out through other structures. Clinically when the outflow pathways are blocked, hydrocephalus (infants) or intracranial hypertension (adults) results. There are endogenous mechanisms that reduce Na,K-ATPase activity in the choroid plexus that we will investigate, including thirst, vasopressin, serotonin, and carbachol. The proposed research has three complementary thrusts. The first aim uses the tools of biochemistry, primary cultures, and genetic manipulation of cells to test the hypothesis that choroid plexus Na,K-ATPase is regulated by kinase-mediated phosphorylation of an accessory protein, phospholemman (FXYD1), with a change in the kinetics of the enzyme. Comparison of cultures from wild type and phospholemman knockout mice will allow direct and indirect effects to be separated. The second aim uses the tools of microscopy and biochemistry to investigate whether the regulation entails redistribution from microvilli to a subapical compartment. The third aim uses wild type, phospholemman knockout, and hydrocephalic mice to test the hypothesis that phospholemman is an obligatory link to regulation of both Na,K-ATPase and choroid cell activation state. The aims test several hypotheses: 1) that there is concerted regulation of Na,K-ATPase and morphological change at the apical brush border through macromolecular complexes;2) that the phospholemman knockout mouse has defective responses to physiological signals to inhibit Na,K-ATPase and change choroid cell morphology;and 3) that a mouse strain that develops hydrocephalus shows enhanced phospholemman phosphorylation, increased cell morphology changes, and reductions in Na,K-ATPase. Relevance: A better understanding of these basic mechanisms in the CSF-secreting organ is needed to facilitate new discoveries of ways to reduce CSF secretion, either to replace surgical shunts or to at least stabilize fragile infants prior to surgery.
Funding Period: 2007-08-15 - 2011-03-31
more information: NIH RePORT

Top Publications

  1. pmc Psychiatric disorders in rapid-onset dystonia-parkinsonism
    Allison Brashear
    Department of Neurology, Wake Forest School of Medicine, Wake Forest Baptist Health, Winston Salem, NC, USA
    Neurology 79:1168-73. 2012
  2. pmc Hyperplasia of pancreatic beta cells and improved glucose tolerance in mice deficient in the FXYD2 subunit of Na,K-ATPase
    Elena Arystarkhova
    Laboratory Membrane Biology, Massachusetts General Hospital, Boston, Massachusetts 2114, USA
    J Biol Chem 288:7077-85. 2013
  3. pmc FXYD proteins reverse inhibition of the Na+-K+ pump mediated by glutathionylation of its beta1 subunit
    Stephanie Bibert
    Department of Pharmacology and Toxicology, University of Lausanne, Lausanne 1005, Switzerland
    J Biol Chem 286:18562-72. 2011
  4. pmc Post-transcriptional control of Na,K-ATPase activity and cell growth by a splice variant of FXYD2 protein with modified mRNA
    Kathleen J Sweadner
    Laboratory of Membrane Biology, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    J Biol Chem 286:18290-300. 2011
  5. pmc New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism
    Richard L Barbano
    Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA
    Parkinsonism Relat Disord 18:737-41. 2012

Detail Information

Publications5

  1. pmc Psychiatric disorders in rapid-onset dystonia-parkinsonism
    Allison Brashear
    Department of Neurology, Wake Forest School of Medicine, Wake Forest Baptist Health, Winston Salem, NC, USA
    Neurology 79:1168-73. 2012
    ..This study examines psychiatric morbidity for 23 patients with RDP in 10 families with family member control subjects and in 3 unrelated patients with RDP, totaling 56 individuals...
  2. pmc Hyperplasia of pancreatic beta cells and improved glucose tolerance in mice deficient in the FXYD2 subunit of Na,K-ATPase
    Elena Arystarkhova
    Laboratory Membrane Biology, Massachusetts General Hospital, Boston, Massachusetts 2114, USA
    J Biol Chem 288:7077-85. 2013
    ..Thus we suggest that in pancreatic beta cells FXYD2 plays a role in Akt signaling pathways associated with cell growth and proliferation...
  3. pmc FXYD proteins reverse inhibition of the Na+-K+ pump mediated by glutathionylation of its beta1 subunit
    Stephanie Bibert
    Department of Pharmacology and Toxicology, University of Lausanne, Lausanne 1005, Switzerland
    J Biol Chem 286:18562-72. 2011
    ..By facilitating deglutathionylation of the β(1) subunit, FXYD proteins reverse oxidative inhibition of the Na(+)-K(+) pump and play a dynamic role in its regulation...
  4. pmc Post-transcriptional control of Na,K-ATPase activity and cell growth by a splice variant of FXYD2 protein with modified mRNA
    Kathleen J Sweadner
    Laboratory of Membrane Biology, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    J Biol Chem 286:18290-300. 2011
    ..The data confirm truncation of FXYD2b as a potential mechanism to regulate the amount of FXYD2 at the cell surface to control activity of Na,K-ATPase and cell growth...
  5. pmc New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism
    Richard L Barbano
    Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA
    Parkinsonism Relat Disord 18:737-41. 2012
    ..Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized...