Kathleen J. Sweadner, Ph.D.

Associate Professor of Cellular and Molecular Physiology in the Dept of Surgery

Massachusetts General Hospital - East
Laboratory of Membrane Biology, Thier-415
55 Fruit St
Boston, MA 02114
Phone: 617-726-8579
Fax: 617- 726-7526
Email: sweadner@helix.mgh.harvard.edu
Predocs: 0 Postdocs: 3 Completed PhD's: 0

The active transport of Na+ and K+ across the plasma membrane is carried out by an ATP-hydrolyzing enzyme, the Na,K-ATPase. We found that multiple isoforms of the enzyme are expressed in the nervous system. Our research follows several related paths: the control of isoform expression; the regulation of the different isoforms; and the molecular structure of the protein.

Na,K-ATPase isoform expression is regulated both developmentally and in response to environmental factors. For example, a particular isoform known as alpha2 is expressed in glia only when complex glial phenotypes are expressed in culture. We have raised antibodies to all of the subunits expressed in brain, and localized them with confocal microscopy.

Isoform-specific regulation by second messengers, including nitric oxide, may be the key to understanding their physiological significance. We have identified two protein kinase phosphorylation sites. We have shown that a small, Isk-like membrane proteins associated with Na,K-ATPase are responsible for important physiological differences between tissues. Using a genomic approach, we define their gene family and identified two new gene products (FXYD6 and FXYD7), which are expressed predominantly in the brain.

Knockout mice and human mutations are new tools leading to insights into sodium pump function. Together, these biochemical and molecular approaches help to elucidate the detailed roles of an enzyme that is of crucial importance in all animal cells, particularly in regulating the physiology of neurons and transporting epithelia.

References:

• Sweadner, KJ, Rael, E. The FXYD gene family of ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression. Genomics, 2000, 68: 41-56.
• Feschenko, MS, Stevenson, EK, Sweadner, KJ. Interaction of protein kinase C and cAMP-dependent pathways in the phosphorylation of the Na,K-ATPase. J.Biol.Chem. 2000 275: 34,693-34,700
• Ellis, DZ, Rabe, JR, Sweadner, KJ. Global loss of Na,K-ATPase and its nitric oxide-mediated regulation in a transgenic mouse model of amyotrophic lateral sclerosis. J. Neurosci. 2003, 23: 43-51.
• Feschenko, MS, Donnet, C, Wetzel, RK, Asinovski, NK, Jones, LR, Sweadner, KJ. Phospholemman, a single-span membrane protein, is an accessory protein of Na,K-ATPase in cerebellum and choroid plexus. J. Neurosci. 2003, 23: 2161-2169.
• Moseley, AE, Lieske, SP, Wetzel, RK, James, PF, He, S, Boivin, GP, Witte, DP, Ramirez, JM, Sweadner, KJ, Lingrel, JB. Na,K-ATPase a2 isoform is expressed in neurons and its absence disrupts neuronal activity in newborn mice. J.Biol.Chem. 2003: 278: 5317-5324.