Michael Harris Nathanson, MD, PhD

Research Interests

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

Research Organizations

Cell Biology: Membrane Traffic

Internal Medicine: Digestive Diseases | Liver Center

Faculty Research

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.

  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.

• Hormonal regulation of nuclear permeability.

  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.

• c-Met must translocate to the nucleus to initiate Ca2+ signals.

  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.

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

  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.

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

  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.

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

  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.

• Nuclear and cytosolic calcium are regulated independently.

  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.

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

  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.

Full List of PubMed Publications

• Fonseca MC, França A, Florentino RM, Fonseca RC, Melo AC, Vidigal PTV, Oliveira AG, Dubuquoy L, Nathanson MH, Leite MF: Cholesterol-enriched membrane microdomains are needed for insulin signaling and proliferation in hepatic cells. Am J Physiol Gastrointest Liver Physiol. 2018 Feb 22; 2018 Feb 22. PMID: 29471671
• Khamphaya T, Chukijrungroat N, Saengsirisuwan V, Mitchell-Richards KA, Robert ME, Mennone A, Ananthanarayanan M, Nathanson MH, Weerachayaphorn J: Nonalcoholic fatty liver disease impairs expression of the type II inositol 1,4,5-trisphosphate receptor. Hepatology. 2017 Oct 10; 2017 Oct 10. PMID: 29023819
• Ruan HB, Ma Y, Torres S, Zhang B, Feriod C, Heck RM, Qian K, Fu M, Li X, Nathanson MH, Bennett AM, Nie Y, Ehrlich BE, Yang X: Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. Genes Dev. 2017 Aug 15; 2017 Sep 13. PMID: 28903979
• Iwakiri Y, Nathanson MH: Alcohol and calcium make a potent cocktail. J Physiol. 2017 May 15; 2017 Apr 18. PMID: 28295353
• Kruglov E, Ananthanarayanan M, Sousa P, Weerachayaphorn J, Guerra MT, Nathanson MH: Type 2 inositol trisphosphate receptor gene expression in hepatocytes is regulated by cyclic AMP. Biochem Biophys Res Commun. 2017 May 6; 2017 Mar 19. PMID: 28327356
• Feriod CN, Oliveira AG, Guerra MT, Nguyen L, Richards KM, Jurczak MJ, Ruan HB, Camporez JP, Yang X, Shulman GI, Bennett AM, Nathanson MH, Ehrlich BE: Hepatic Inositol 1,4,5 Trisphosphate Receptor Type 1 Mediates Fatty Liver. Hepatol Commun. 2017 Feb; 2016 Nov 11. PMID: 28966992
• Khamphaya T, Chansela P, Piyachaturawat P, Suksamrarn A, Nathanson MH, Weerachayaphorn J: Effects of andrographolide on intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats. Eur J Pharmacol. 2016 Oct 15; 2016 Jul 27. PMID: 27475677
• Nathanson MH, Terrault N: Hepatitis B surface antigen loss: Not all that we hoped it would be. Hepatology. 2016 Aug; 2016 Jun 16. PMID: 27178231
• Omary MB, Cohen DE, El-Omar E, Jalan R, Low M, Nathanson M, Peek R, Turner J: Not All Mice Are the Same: Standardization of Animal Research Data Presentation. Gut. 2016 Jun. PMID: 27197119
• 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 Jul; 2015 Mar 18. PMID: 25796361
• Guerra MT, Nathanson MH: Calcium signaling and secretion in cholangiocytes. Pancreatology. 2015 Jul; 2015 Jun 12. PMID: 26100660
• Nathanson MH: What is Hepatology looking for? Hepatology. 2015 Apr; 2015 Mar 10. PMID: 25581014
• 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. J Biol Chem. 2015 Jan 2; 2014 Nov 5. PMID: 25378392
• Feriod CN, Nguyen L, Jurczak MJ, Kruglov EA, Nathanson MH, Shulman GI, Bennett AM, Ehrlich BE: Inositol 1,4,5-trisphosphate receptor type II (InsP3R-II) is reduced in obese mice, but metabolic homeostasis is preserved in mice lacking InsP3R-II. Am J Physiol Endocrinol Metab. 2014 Dec 1; 2014 Oct 14. PMID: 25315698
• 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; 2014 Dec 1. PMID: 25437447
• Amaya MJ, Nathanson MH: Calcium signaling and the secretory activity of bile duct epithelia. Cell Calcium. 2014 Jun; 2014 Feb 12. PMID: 24612866
• Chen J, Wong S, Nathanson MH, Jain D: Evaluation of Barrett esophagus by multiphoton microscopy. Arch Pathol Lab Med. 2014 Feb. PMID: 24476518
• 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. 2014 Jan; 2013 Jul 29. PMID: 23839970
• Amaya MJ, Nathanson MH: Calcium signaling in the liver. Compr Physiol. 2013 Jan. PMID: 23720295
• Shieh FK, Drumm H, Nathanson MH, Jamidar PA: High-definition confocal endomicroscopy of the common bile duct. J Clin Gastroenterol. 2012 May-Jun. PMID: 22011583
• Kruglov EA, Gautam S, Guerra MT, Nathanson MH: Type 2 inositol 1,4,5-trisphosphate receptor modulates bile salt export pump activity in rat hepatocytes. Hepatology. 2011 Nov; 2011 Aug 30. PMID: 21748767
• Andrade V, Guerra M, Jardim C, Melo F, Silva W, Ortega JM, Robert M, Nathanson MH, Leite F: Nucleoplasmic calcium regulates cell proliferation through legumain. J Hepatol. 2011 Sep; 2011 Jan 13. PMID: 21237226
• Loeser CS, Robert ME, Mennone A, Nathanson MH, Jamidar P: Confocal endomicroscopic examination of malignant biliary strictures and histologic correlation with lymphatics. J Clin Gastroenterol. 2011 Mar. PMID: 21063210
• Mennone A, Nathanson MH: Needle-based confocal laser endomicroscopy to assess liver histology in vivo. Gastrointest Endosc. 2011 Feb; 2010 Dec 8. PMID: 21145055
• Reed AM, Husain SZ, Thrower E, Alexandre M, Shah A, Gorelick FS, Nathanson MH: Low extracellular pH induces damage in the pancreatic acinar cell by enhancing calcium signaling. J Biol Chem. 2011 Jan 21; 2010 Nov 17. PMID: 21084290
• Fiedler MJ, Nathanson MH: The type I inositol 1,4,5-trisphosphate receptor interacts with protein 4.1N to mediate neurite formation through intracellular Ca waves. Neurosignals. 2011; 2011 Mar 10. PMID: 21389686
• Cruz LN, Guerra MT, Kruglov E, Mennone A, Garcia CR, Chen J, Nathanson MH: Regulation of multidrug resistance-associated protein 2 by calcium signaling in mouse liver. Hepatology. 2010 Jul. PMID: 20578149
• Soliman EM, Rodrigues MA, Gomes DA, Sheung N, Yu J, Amaya MJ, Nathanson MH, Dranoff JA: Intracellular calcium signals regulate growth of hepatic stellate cells via specific effects on cell cycle progression. Cell Calcium. 2009 Mar; 2009 Jan 7. PMID: 19131107
• Rodrigues MA, Gomes DA, Andrade VA, Leite MF, Nathanson MH: Insulin induces calcium signals in the nucleus of rat hepatocytes. Hepatology. 2008 Nov. PMID: 18798337
• 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. J Biol Chem. 2008 Feb 15; 2007 Dec 11. PMID: 18073207
• Rogart JN, Nagata J, Loeser CS, Roorda RD, Aslanian H, Robert ME, Zipfel WR, Nathanson MH: Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo. Clin Gastroenterol Hepatol. 2008 Jan; 2007 Dec 18. PMID: 18065276
• Minagawa N, Nagata J, Shibao K, Masyuk AI, Gomes DA, Rodrigues MA, Lesage G, Akiba Y, Kaunitz JD, Ehrlich BE, Larusso NF, Nathanson MH: Cyclic AMP regulates bicarbonate secretion in cholangiocytes through release of ATP into bile. Gastroenterology. 2007 Nov; 2007 Aug 14. PMID: 17916355
• Garcia-Tsao G, Nathanson MH: Portal hypertension: from the patient to the molecule and back: a symposium honoring Roberto J. Groszmann, MD. J Clin Gastroenterol. 2007 Nov-Dec. PMID: 17975470
• Correa PR, Kruglov EA, Thompson M, Leite MF, Dranoff JA, Nathanson MH: Succinate is a paracrine signal for liver damage. J Hepatol. 2007 Aug; 2007 Apr 5. PMID: 17451837
• Nagata J, Guerra MT, Shugrue CA, Gomes DA, Nagata N, Nathanson MH: Lipid rafts establish calcium waves in hepatocytes. Gastroenterology. 2007 Jul; 2007 Apr 11. PMID: 17631147
• Rodrigues MA, Gomes DA, Leite MF, Grant W, Zhang L, Lam W, Cheng YC, Bennett AM, Nathanson MH: Nucleoplasmic calcium is required for cell proliferation. J Biol Chem. 2007 Jun 8; 2007 Apr 9. PMID: 17420246
• Husain SZ, Grant WM, Gorelick FS, Nathanson MH, Shah AU: Caerulein-induced intracellular pancreatic zymogen activation is dependent on calcineurin. Am J Physiol Gastrointest Liver Physiol. 2007 Jun; 2007 Mar 1. PMID: 17332472
• Kruglov EA, Correa PR, Arora G, Yu J, Nathanson MH, Dranoff JA: Molecular basis for calcium signaling in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2007 Apr; 2007 Jan 4. PMID: 17204544
• Hernandez E, Leite MF, Guerra MT, Kruglov EA, Bruna-Romero O, Rodrigues MA, Gomes DA, Giordano FJ, Dranoff JA, Nathanson MH: The spatial distribution of inositol 1,4,5-trisphosphate receptor isoforms shapes Ca2+ waves. J Biol Chem. 2007 Mar 30; 2007 Feb 6. PMID: 17284437
• O'Brien EM, Gomes DA, Sehgal S, Nathanson MH: Hormonal regulation of nuclear permeability. J Biol Chem. 2007 Feb 9; 2006 Dec 7. PMID: 17158097
• Marius P, Guerra MT, Nathanson MH, Ehrlich BE, Leite MF: Calcium release from ryanodine receptors in the nucleoplasmic reticulum. Cell Calcium. 2006 Jan; 2005 Nov 9. PMID: 16289270
• Sehgal S, Guerra MT, Kruglov EA, Wang J, Nathanson MH: Protein 4.1N does not interact with the inositol 1,4,5-trisphosphate receptor in an epithelial cell line. Cell Calcium. 2005 Nov. PMID: 16122796
• Husain SZ, Prasad P, Grant WM, Kolodecik TR, Nathanson MH, Gorelick FS: The ryanodine receptor mediates early zymogen activation in pancreatitis. Proc Natl Acad Sci U S A. 2005 Oct 4; 2005 Sep 26. PMID: 16186498
• Minagawa N, Kruglov EA, Dranoff JA, Robert ME, Gores GJ, Nathanson MH: The anti-apoptotic protein Mcl-1 inhibits mitochondrial Ca2+ signals. J Biol Chem. 2005 Sep 30; 2005 Jul 18. PMID: 16027162
• Correa PR, Guerra MT, Leite MF, Spray DC, Nathanson MH: Endotoxin unmasks the role of gap junctions in the liver. Biochem Biophys Res Commun. 2004 Sep 24. PMID: 15336523
• Shibao K, Hirata K, Robert ME, Nathanson MH: Loss of inositol 1,4,5-trisphosphate receptors from bile duct epithelia is a common event in cholestasis. Gastroenterology. 2003 Oct. PMID: 14517800
• Echevarría W, Leite MF, Guerra MT, Zipfel WR, Nathanson MH: Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nat Cell Biol. 2003 May. PMID: 12717445
• Hirata K, Dufour JF, Shibao K, Knickelbein R, O'Neill AF, Bode HP, Cassio D, St-Pierre MV, Larusso NF, Leite MF, Nathanson MH: Regulation of Ca(2+) signaling in rat bile duct epithelia by inositol 1,4,5-trisphosphate receptor isoforms. Hepatology. 2002 Aug. PMID: 12143036
• Pusl T, Wu JJ, Zimmerman TL, Zhang L, Ehrlich BE, Berchtold MW, Hoek JB, Karpen SJ, Nathanson MH, Bennett AM: Epidermal growth factor-mediated activation of the ETS domain transcription factor Elk-1 requires nuclear calcium. J Biol Chem. 2002 Jul 26; 2002 Apr 23. PMID: 11971908
• O'Neill AF, Hagar RE, Zipfel WR, Nathanson MH, Ehrlich BE: Regulation of the type III InsP(3) receptor by InsP(3) and calcium. Biochem Biophys Res Commun. 2002 Jun 14. PMID: 12056830
• Hirata K, Pusl T, O'Neill AF, Dranoff JA, Nathanson MH: The type II inositol 1,4,5-trisphosphate receptor can trigger Ca2+ waves in rat hepatocytes. Gastroenterology. 2002 Apr. PMID: 11910359

Edit this profile