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Research Interests

Magnesium is one of the most abundant cations in mammalian cells. Its importance is underscored by the many enzymes, transporters, and receptors that require magnesium as a cofactor or are regulated by it. Despite its influence on many cellular and disease processes, our understanding of magnesium homeostasis lags far behind that of other biologically important cations, largely because the transporters of magnesium have not been identified at the molecular level. Furthermore, little work has been conducted regarding the effects of magnesium deficiency on gene expression, especially with respect to its role in assorted pathologies. Gene expression profiling using cDNA microarrays represents a powerful method for identifying genes involved in specific cellular or disease processes. We are using this technology to compare global gene expression patterns of select tissues of normal mice to their counterparts from magnesium deficient mice in order to identify genes that are differentially expressed under the two conditions. Using this approach it should be possible to identify genes involved in magnesium homeostasis, including those encoding magnesium transporters and other proteins that provide compensation during magnesium depletion. Genes that are aberrantly expressed under magnesium restricted conditions, and which contribute to various pathological conditions associated with magnesium deficiency should also be identified.

Selected Publications

Woo AL, Noonan WT, Schultheis PJ, Neumann JC, Manning PA, Lorenz JN, Shull GE. Renal function in NHE3-deficient mice with transgenic rescue of small intestinal absorptive defect. Am J Physiol Renal Physiol. 2003 Jun;284(6):F1190-8. Epub 2003 Feb 11.

Shull, G.E., Miller, M.L., Schultheis, P.J. Lessons from genetically engineered animal models: absorption and secretion of ions in the gastrointestinal tract. Am J Physiol. Gastrointest Liver Physiol. 2000 Feb;278(2):G185-90. Review.

Melvin J.E., Park K., Richardson L., Schultheis P.J., Shull G.E. Mouse down-regulated in adenoma (DRA) is an intestinal Cl(-)/HCO(3)(-) exchanger and is up-regulated in colon of mice lacking the NHE3 Na(+)/H(+) exchanger. J Biol Chem. 274:22855-61, 1999.

Baird, N.R., Orlowski, J., Szabo, E.Z., Zaun, H.C., Schultheis, P.J., Menon, A.G., and Shull, G.E. Molecular Cloning, Genomic Organization, and Functional Expression of Na⁺/H⁺ Exchanger Isoform 5 (NHE5) from Human Brain. J. Biol. Chem. 274: 4377-4382, 1999.

Schultheis, P.J., Lorenz, J., Meneton, P., Riddle, T.M., Duffy, J., Doetschman, T., Flagella, M., Nieman, M., Miller, M.L., and Shull, G.E. Phenotype Resembling Gitelman’s Syndrome in Mice Lacking the Apical Na⁺-Cl^- Cotransporter of the Distal Convoluted Tubule. J. Biol. Chem. 273:29150-29155, 1998.

Schultheis, P.J., Clarke, L.L., Meneton, P., Miller, M.L., Harline, M., Soleimani, M., Riddle, T., Duffy, J.J., Doetschman, T., Wang, T., Giebisch, G., Aronson, P.S., Lorenz, J., and Shull, G.E. Renal and Intestinal Absorptive Defects in Mice Lacking the NHE3 Na⁺/H⁺ Exchanger. Nature Genet. 19: 282-285, 1998.

Schultheis, P.J., Clarke, L.L., Meneton, P., Harline, M., Boivin, G.P., Stemmermann, G., Duffy, J.J., Doetschman, T., Miller, M.L., and G.E. Shull. Targeted Disruption of the Murine Na⁺/H⁺Exchanger Isoform 2 Gene Causes Reduced Viability of Gastric Parietal Cells and Loss of Net Acid Secretion. J. Clin. Invest. 101: 1243-1253, 1998.

Wang, Z., Schultheis, P.J., and Shull, G. Three N-terminal Variants of the AE2 Cl^-/HCO3^-Exchanger are Encoded by mRNAs Transcribed from Alternative Promoters. J. Biol. Chem. 271: 7835-7843, 1996.

Johnson, C. L., Schultheis, P.J., Lingrel, J. B., Johnson, C. G., and Wallick, E.T. Comparison of the Effects of Potassium on Ouabain Binding to Native and Site-directed Mutants of Na, K-ATPase. Arch. Biochem. Biophys. 317: 133-141, 1995.

Schultheis, P.J., Wallick, E.T., and Lingrel, J.B. Kinetic Analysis of Ouabain Binding to Native and Mutated Forms of Na,K-ATPase and Identification of a New Region Involved in Cardiac Glycoside Interactions. J. Biol. Chem. 268: 22686-22694, 1993.

Schultheis, P.J. and Lingrel, J.B. Substitution of Transmembrane Residues with Hydrogen Bonding Potential in the a Subunit of Na,K-ATPase Reveals Alterations in Ouabain Sensitivity. Biochem. 32: 544-550, 1993.