Michael H. Nathanson, M.D., Ph.D

Professor, Internal Medicine/Section of Infectious Diseases, and Cell Biology Chief, Section of Digestive Diseases, Internal Medicine Director, Center of Cellular and Molecular Imaging (CCMI)
Phone: (203) 785-7312 Lab: (203) 785-5308/ -6051 Fax: (203) 785-4306 e-mail: michael.nathanson@Yale.edu		Section of Digestive Diseases Department of Internal Medicine Yale University School of Medicine 333 Cedar Street PO Box 208019 New Haven, CT 06520-8019 <Courier Address> 300 Cedar Street, TAC S241D (Lab: TAC S230) New Haven, CT 06519-1612

Ca2+ is a ubiquitous second messenger that regulates a wide range of activities in virtually every type of cell. For example, in hepatocytes Ca2+ regulates such varied processes as bile acid transport, bile secretion, exocytosis, paracellular permeability, canalicular contraction, glucose metabolism, mitochondrial redox state, gene transcription, cell growth, and apoptosis. How does a single second messenger coordinate such diverse effects within a single cell? It is now believed that the spatial and temporal patterns of Ca2+ signals, such as Ca2+ waves, gradients, and oscillations determine the specificity of these signals. For example, Ca2+ waves direct apical Cl- secretion in pancreatic acinar cells, while Ca2+ gradients regulate exocytosis in acinar cells and neurons, cell motion in neural growth cones and keratocytes, and localized activation of calmodulin in fibroblasts. Localized increases in Ca2+ in subcellular regions such as the nucleus can furthermore activate specific transcription factors or nuclear kinases. The frequency of Ca2+ oscillations also encodes signaling information, and can differentially regulate transcription of genes such as IL-2 and IL-8 and control exocrine secretion. The research focus in our laboratory is to determine the molecular and cellular basis for such Ca2+ signaling patterns in the liver, and to define how these patterns regulate specific, clinically relevant cell functions, including bile secretion and hepatic regeneration.

Our laboratory is involved in three main projects. First, we are examining the factors that organize Ca2+ waves in hepatocytes, the principal parenchymal cell of the liver. Ca2+ signals in the hepatocyte are mediated entirely by inositol 1,4,5-trisphosphate (InsP3). InsP3 acts by binding to the InsP3 receptor (InsP3R), which is a tetrameric InsP3-gated Ca2+ release channel in the membrane of the endoplasmic reticulum (Figure 1). Two of the three known isoforms of the InsP3R (InsP3R-1 and InsP3R-2) are expressed in hepatocytes, each with distinct biophysical properties. Each of these two isoforms is distributed in a distinctive subcellular pattern in the hepatocyte, which thus may establish signaling microdomains within the cell. The hypothesis of this project is that Ca2+ signaling patterns and their effects on hepatocyte bile secretion depend upon the types of InsP3Rs that are expressed and their subcellular distributions.

Second, we are examining the organization and effects of Ca2+ waves in cholangiocytes, the second type of epithelium in liver, and which lines the biliary tree. The hypothesis of this project is that the specific subcellular distribution of InsP3R isoforms in cholangiocytes regulates the subcellular pattern of Ca2+ signals, which in turn regulates ductular secretion. Recent work in our laboratory indeed suggests that loss of InsP3Rs is a common feature in animal models of cholestasis and in a range of human cholestatic disorders, including primary biliary cirrhosis, sclerosing cholangitis, biliary atresia, and common bile duct obstruction. These studies thus attempt to define the molecular mechanism by which altered Ca2+ signaling impairs tissue function in disease states.

Third, we are examining the mechanisms and effects of Ca2+ signals in the nucleus. The liver displays a unique ability to grow and regenerate. For example, complete hepatic regeneration occurs within days to weeks after most of the organ has been removed. The hypothesis of this project is that Ca2+ in the nucleoplasm is regulated by distinct nuclear InsP3Rs, and that nuclear rather than cytosolic Ca2+ regulates cell growth. We have reported that the nuclear interior contains a reticular network of InsP3-sensitive Ca2+ stores, so that there is the potential to generate localized subnuclear Ca2+ signals, analogous to the Ca2+ puffs that can occur in the cytosol. We currently are working to define the endogenous mechanisms that activate Ca2+ signals that are localized to the nucleus, and to define the ways in which these signals affect cell growth.

Recent publications
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Leite, M.F., Thrower, E.C., Echevarria, W., Koulen, P., Hirata, Bennett, A.M., Ehrlich, B.E., and Nathanson, M.H. (2003) Nuclear and cytosolic calcium are regulated independently. Proc. Natl. Acad. Sci. USA 100: 2975-2980.  

Echevarria, W., Leite, M.F., Guerra, M.T., Zipfel, W.R., and Nathanson, M.H. (2003) Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nat. Cell Biol. 5:440-446.

Shibao, K., Hirata, K., Robert, M.E., and Nathanson, M.H. (2003)  Loss of inositol 1,4,5-trisphosphate receptors is a final common pathway for cholestasis. Gastroenterology 125:1175-1187. 

Leite, M.F., Hirata, K., Pusl, T., Burgstahler, A.D., Okazaki, K., Ortega, J.M., Goes, A.M., Prado, M.A., Spray, D.C., and Nathanson MH. (2002) Molecular basis for pacemaker cells in epithelia. J. Biol. Chem. 277:16313-16323. 

Leite, M.F., Burgstahler, A.D., and Nathanson, M.H. (2002) Ca2+ waves require sequential activation of inositol trisphosphate receptors and ryanodine receptors in pancreatic acinar cells. Gastroenterology 122:415-427. 

Hirata, K., Pusl, T., O’Neill, A.F., Dranoff, J.A., and Nathanson, M.H. (2002) The type II inositol 1,4,5-trisphosphate receptor can trigger Ca2+ waves in hepatocytes. Gastroenterology 122:1088-1100.

Hirata, K., Dufour, J.F., Shibao, K., Knickelbein, R., O'Neill, A.F., Bode, H.P., Cassio, D., St-Pierre, M.V., Larusso, N.F., Leite, M.F., and Nathanson, M.H. (2002) Regulation of Ca2+ signaling in bile duct epithelia by inositol 1,4,5-trisphosphate isoforms. Hepatology 36:284-296. 

Pusl, T., Wu, J.J., Zimmermann, T., Zhang, L., Ehrlich, B.E., Berchtold, M.W., Hoek, J. B., Karpen, S.J., Nathanson, M.H., and Bennett, A. M. (2002)  Epidermal growth factor-mediated activation of the ETS-domain transcription factor Elk-1 requires nuclear calcium. J. Biol. Chem. 277: 27517-27527.

Bode, H.P., Cassio, D., Leite, M.F., St.-Pierre, M.V., Hirata, K., Okazaki, K., Sears, M.L., Nathanson, M.H., and Dufour, J.F. (2002) Expression and regulation of gap junctions in rat cholangiocytes. Hepatology 36:631-640

Leite, M.F. and Nathanson, M.H. (2002) Of sweat and bile. J. Hepatol. 37:705-7072. 

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