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

Professor of Medicine and Cell Biology
Chief, Section of Digestive Diseases
Section of Digestive Diseases and Cell Biology
more on this physician

Research Interests

My laboratory is interested in the mechanisms and effects of calcium signals in polarized epithelia. One aspect of our work is to define how calcium signals are differentially regulated in the nucleus and cytoplasm. This involves identification of distinct calcium stores and release mechanisms in the nucleus, and we are examining whether and how these are activated selectively by growth factors. Long-range plans are to determine the relative effects of nuclear and cytoplasmic calcium signals on cell growth. The second aspect of our work is to examine how calcium waves and other types of calcium signals regulate secretion in polarized epithelia. Calcium waves preferentially begin in the apical region of most secretory epithelia, and we are in the process of defining the mechanisms responsible for this. We also are using an adenoviral antisense approach to understand the relative roles of each inositol 1,4,5-trisphosphate receptor isoform in regulating calcium signaling and secretion in vitro and in vivo. The long-range goal of all of these studies is to determine how the spatial organization of calcium signals regulates organ function, and to examine whether altered calcium signaling patterns are responsible for impairments in tissue regeneration and secretion in certain disease states.

Another major focus is to examine intercellular communication of second messenger signals and to establish the mechanism by which gap junctions act to in coordinating the intercellular spread of Ca2+ waves in isolated pairs and triplets of cells. These studies are being extended to characterize the organization of intercellular Ca2+ waves both in intact organs and in cell lines expressing different types of gap junction proteins. The long range goal of all of these studies is to determine how the spatial organization of Ca2+ signals regulates secretion by epithelia, and to examine whether altered Ca2+ signaling patterns are responsible for impaired secretion in certain disease states.

Selected Publications

• Leite, M.F., Thrower, E.C., Echevarria, W., Koulen, P., Hirata, Bennett, A.M., Ehrlich, B.E., and Nathanson, M.H.: Nuclear and cytosolic calcium are regulated independently. Proc. Natl. Acad. Sci. USA 100:2975-2980, 2003.
• Echevarria, W., Leite, M.F., Guerra, M.T., Zipfel, W.R., and Nathanson, M.H.: Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nature Cell Biology 5:440-446, 2003.
• Rodrigues, M.A., Gomes, D.A., Grant, W., Leite, M.F., Bennett, A.M., Zhang, L., Lam, W., Cheng, Y.-C., and Nathanson, M.H.: Nucleoplasmic calcium regulates cell growth. J. Biol. Chem. 282:17061-17068, 2007.
• O‚Brien, E.M., Gomes, D.A., Sehgal, S., and Nathanson, M.H.: Hormonal regulation of nuclear permeability. J. Biol. Chem. 282:4210-4217, 2007.
• Hernandez, E., Leite, M.F., Guerra, M.T., Kruglov, E.A., Bruna-Romero, O., Rodrigues, M.A., Gomes, D.A., Giordano, F.J., Dranoff, J.A., and Nathanson, M.H.: The spatial distribution of inositol 1,4,5-trisphosphate receptor isoforms shapes Ca2+ waves. J. Biol. Chem. 282:10057-10067, 2007.
• Nagata, J., Guerra, M.T., Shugrue, C.A., Gomes, D.A., and Nathanson, M.H.: Lipid rafts establish calcium waves in hepatocytes. Gastroenterology 133:256-267, 2007.
• Minagawa, N., Nagata, J., Shibao, K., Masyuk, A.I., Gomes, D.A., Kaunitz, J.D., LeSage, G., Ehrlich, B.E., LaRusso, N.F., and Nathanson, M.H.: Cyclic AMP regulates bicarbonate secretion in cholangiocytes through release of ATP into bile. Gastroenterology 133:1592-1602, 2007.
• Gomes, D.A., Rodrigues, M.A., Leite, M.F., Gomez, M.V., Varnai, P., Balla, T., Bennett, A.M., and Nathanson, M.H.: c-met must translocate to the nucleus to initiate Ca2+ signals. J. Biol. Chem., in press.

Contact

Campus Address
Department of Internal Medicine
333 Cedar Street (LMP 1080)
New Haven, CT 06520

E-mail
michael.nathanson@yale.edu

Office Phone
(203) 785-7312