Cell Nucleus; Cell Biology; Digestive System Diseases; Liver; Calcium Signaling; Hepatocytes
My laboratory studies 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. The second aspect of our work is to examine how calcium waves and other 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 IP3 receptor isoform in regulating calcium signaling and secretion in vitro and in vivo. Another major focus is to examine intercellular communication of second messenger signals and to establish the mechanism by which gap junctions act in coordinating intercellular spread of Ca2+ waves in isolated pairs and triplets of cells.
Specialized Terms: Mechanisms and effects of calcium signals in polarized epithelia; Effect of spatial organization of calcium signals on organ function regulation; Factors that organize Ca2+ waves in hepatocytes; Organization and effects of Ca2+ waves in cholangiocytes; Mechanisms and effects of Ca2+ signals in the nucleus
Extensive Research Description
- NIH P01 DK57751 (PI: M.H. Nathanson). Regulation of liver by nuclear calcium signaling. Duration: 4/1/06-3/31/11. The major goals of this project are to determine the mechanisms by which calcium is regulated in the nucleus of hepatocytes, and to determine the functional effects of nuclear calcium signals in liver.
- NIH R01 DK45710 (PI: M.H. Nathanson). Calcium waves in hepatocytes: mechanisms and effects. Duration: 4/1/10-3/31/15. The major goals of this project are to determine the subcellular location and function of the different InsP3 receptor isoforms in hepatocytes and to determine if the different isoforms exert distinct effects on organization of calcium waves and regulation of secretion by calcium.
- NIH R01 DK61747 (PI: B.E. Ehrlich, M.H. Nathanson [multiple PI’s] ). Regulation of cholangiocytes by InsP3 receptor isoforms. Duration: 5/1/09-4/30/13. Dr. Nathanson is co-investigator on this award. The major goals of this project are to determine how InsP3 receptors regulate calcium signaling and bicarbonate secretion in intrahepatic bile ducts.
- 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.
- 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.
- 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. 283:4344-4351, 2008.
- Amaya, M.J., Oliveira, A.G., Guimaraes, E.S., Casteluber, M.C.F., Carvalho, S.M., Andrade, L.M., Pinto, M.C.X., Resende, R.R., Menezes, G.B., Nathanson, M.H., and Leite, M.F.: The insulin receptor translocates to the nucleus to regulate cell proliferation in liver. Hepatology 59:274-283, 2014.
- Amaya, M.J., Oliveira, A.G, Schroeder, L.K., Allgeyer, E.S., Bewersdorf, J., and Nathanson, M.H.: Apical localization of inositol 1,4,5-trisphosphate receptors is independent of extended synaptotagmins in hepatocytes. PLoS One, 1;9(12), 2014.
- Ananthanarayanan, M., Banales, J.M., Guerra, M.T., Spirli, C., Tafur, D., Munoz-Garrido, P., Saez, E. and Nathanson, M.H.: Post-translational regulation of the type III inositol 1,4,5-trisphosphate receptor by miRNA-506. J. Biol. Chem. 290:184-196, 2015.
- 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.
- Weerachayaphorn, J., Amaya, M.J., Spirli, C., Chansela, P., Mitchell, K.A., Ananthanarayanan, M., and Nathanson, M.H.: Nuclear Factor Erythroid 2-like 2 Regulates Expression of Inositol 1,4,5-trisphosphate Receptor, Type 3 and Calcium Signaling in Cholangiocytes. Gastroenterology 149:211-222, 2015.