Michael Nathanson, MD, PhD

Research Interests

Cell Nucleus; Cell Biology; Digestive System Diseases; Liver; Calcium Signaling; Hepatocytes

Research Organizations

Cell Biology: Membrane Traffic

Internal Medicine: Diabetes Research Center | Digestive Diseases | Liver Center

Obesity Research Working Group

Yale Cancer Center: Signal Transduction

Office of Cooperative Research

Research Summary

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.

Selected Publications

• Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum.

  Echevarría W, Leite MF, Guerra MT, Zipfel WR, Nathanson MH. Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nature Cell Biology 2003, 5:440-6. 2003

• Hormonal regulation of nuclear permeability.

  O'Brien EM, Gomes DA, Sehgal S, Nathanson MH. Hormonal regulation of nuclear permeability. The Journal Of Biological Chemistry 2007, 282:4210-7. 2007

• c-Met must translocate to the nucleus to initiate calcium signals.

  Gomes DA, Rodrigues MA, Leite MF, Gomez MV, Varnai P, Balla T, Bennett AM, Nathanson MH. c-Met must translocate to the nucleus to initiate calcium signals. The Journal Of Biological Chemistry 2008, 283:4344-51. 2008

• The insulin receptor translocates to the nucleus to regulate cell proliferation in liver.

  Amaya MJ, Oliveira AG, Guimarães ES, Casteluber MC, Carvalho SM, Andrade LM, Pinto MC, Mennone A, Oliveira CA, Resende RR, Menezes GB, Nathanson MH, Leite MF. The insulin receptor translocates to the nucleus to regulate cell proliferation in liver. Hepatology (Baltimore, Md.) 2014, 59:274-83. 2014

• Apical localization of inositol 1,4,5-trisphosphate receptors is independent of extended synaptotagmins in hepatocytes.

  Amaya MJ, Oliveira AG, Schroeder LK, Allgeyer ES, Bewersdorf J, Nathanson MH. Apical localization of inositol 1,4,5-trisphosphate receptors is independent of extended synaptotagmins in hepatocytes. PloS One 2014, 9:e114043. 2014

• Post-translational regulation of the type III inositol 1,4,5-trisphosphate receptor by miRNA-506.

  Ananthanarayanan M, Banales JM, Guerra MT, Spirli C, Munoz-Garrido P, Mitchell-Richards K, Tafur D, Saez E, Nathanson MH. Post-translational regulation of the type III inositol 1,4,5-trisphosphate receptor by miRNA-506. The Journal Of Biological Chemistry 2015, 290:184-96. 2015

• Nuclear and cytosolic calcium are regulated independently.

  Leite MF, Thrower EC, Echevarria W, Koulen P, Hirata K, Bennett AM, Ehrlich BE, Nathanson MH. Nuclear and cytosolic calcium are regulated independently. Proceedings Of The National Academy Of Sciences Of The United States Of America 2003, 100:2975-80. 2003

• Nuclear Factor, Erythroid 2-Like 2 Regulates Expression of Type 3 Inositol 1,4,5-Trisphosphate Receptor and Calcium Signaling in Cholangiocytes.

  Weerachayaphorn J, Amaya MJ, Spirli C, Chansela P, Mitchell-Richards KA, Ananthanarayanan M, Nathanson MH. Nuclear Factor, Erythroid 2-Like 2 Regulates Expression of Type 3 Inositol 1,4,5-Trisphosphate Receptor and Calcium Signaling in Cholangiocytes. Gastroenterology 2015, 149:211-222.e10. 2015

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