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Education & Experience
2013-present Professor, PKUSZ, China.
2006-2013 Chair Professor, Department of Physiology, University of Hong Kong
2006-present Adjunct Professor, Department of Physiology, University of Minnesota, USA.
1999-2006 Professor, Department of Pharmacology, University of Minnesota, USA.
1990-1999 Professor, Department of Physiology, University of Minnesota, USA.
l986-1990 Associate Professor, Department of Physiology, University of Minnesota, USA.
1981-1986 Assistant Professor, Department of Physiology, University of Minnesota, USA.
1973-1978 Ph.D., Biophysics, University of California at Berkeley, USA.
1971-1973 M.S., Physics, University of California at Berkeley, USA.
1968-1971 B.A., Physics, University of California at Berkeley, USA.
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Awards & Honors
Morningside Lectureship, 5th Morningside Symposium of Frontier Chemical Biology, Shenzhen, China, 2013.
Nishizuka Lecture, 17th International Symposium on Ca2+-Binding Proteins and Ca2+ Function in Health and Disease. Beijing, China, 2011.
Keynote Lecture, FASEB Summer Research Conference on "NAD Metabolism & Signaling", Lucca, Italy, 2011.
Plenary Lecturer, Commemoration of the 60th Anniversary of the Korean Society of Medical Biochemistry and Molecular Biology, Seoul, South Korea, 2008.
Keynote address, Frontiers in Biomedical Research Conference, Hong Kong, 2006.
Academy for Excellence in Health Research, Academic Health Center, University of Minnesota, inducted in 2004. (http://www.ahc.umn.edu/research/academy/members/home.html)
Distinguished McKnight University Professor, University of Minnesota, 1996-2006.
Plenary Lecture, Scandinavian Congress of Physiology, Odense, Denmark, 2003.
Starting Lecture, British Physiological Society Meeting, London, UK, 2002.
Keynote Lecture, 72nd Annual Meeting of Pharmacological Society of Japan, Sapporo, Japan, 1999.
National Institute of Health-USA, Study Section Member, 1992, 1993-1997 and 1999.
Plenary Lecture, FASEB Summer Research Conference on CD38, Vermont, USA, 1998.
Introductory Lecture, 3rd International CD38 Workshop, Paris, France, 1997.
Honorary degree in Medicine and Surgery, University of Genoa, Italy, 1997.
Chair, symposium on cyclic ADP-ribose, ASPET annual meeting, San Diego, 1996.
Eraldo Antonini Lecture, National Biochemical Society, Pavia, Italy, 1994.
EDITORAL BOARDS
Editor-in-Chief, Messenger, 2012-present.
Editorial Board, Journal of Biological Chemistry, 2003-2008, 2014-2018.
Guest editor, special issue on “Calcium Signaling and Cyclic ADP-ribose”, Cell Biochem. Biophys., 1997.
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Research Fields
Molecular and Cellular Physiology、Calcium Signaling
Cells possess various mechanisms for transducing chemical information from the external environment to intracellular responses. Specific receptor proteins are present on cell membranes, which, upon binding of ligands such as hormones or neurotransmitters, can lead to production of second messengers inside the cell. The first such second messenger identified was cyclic AMP. Likewise, receptor activation can also trigger elevation of intracellular calcium, due to mobilization of internal stores. The discovery of inositol trisphosphate (IP3) as a second messenger for this process has formalized the central role of calcium mobilization in cellular signaling. Our research establishes that, in addition to IP3, the internal calcium stores can be mobilized by two new messenger molecules via completely independent pathways.
Cyclic ADP-Ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) were discovered and their structures determined in my laboratory. Cyclic ADP-ribose is a new cyclic nucleotide, but unlike cyclic AMP, its main signaling function is through direct modulation of the calcium-induced calcium release, a major mechanism of calcium mobilization in addition to that mediated by IP3. The structure of cADPR shown on the left was determined by X-ray crystallography and the site of cyclization is at the N1 of the adenine ring.
NAADP is a metabolite of NADP which mobilizes the intracellular calcium stores through yet another totally independent and novel pathway. NAADP is identical to NADP, except with a -COOH (green circle) replacing the -NH2 of the nicotinamide of NADP. The groups critical for its calcium mobilizing activity have been identified and are circled in the structure on the left. Ongoing projects focus on elucidating the mechanisms of the signaling functions of cADPR and NAADP, characterizing their intracellular receptors, and the enzymes involved in their synthesis and degradation.
X-ray Crystallography is used to determine the three dimensional structures of the enzymes involved, such as human CD38 and Aplysia ADP-Ribosyl cyclase, and in combination with site-directed mutagenesis, to unravel the catalytic mechanisms of the synthesis and degradation of these messenger molecules.
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Selected Publications
1. Zhao, Y.J., Lam, C.M.C. and Lee, H.C. (2012) The membrane-bound enzyme CD38 exists in two opposing orientations. Science Signaling 5, ra67. Highlighted as Editor’s Choice in Science 337, 1434, (2012).
2. Lee, H.C. (1997) Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP. Physiol. Rev. 77, 1133-1164. Citations: 295.
3. Prasad, G.S., McRee, D.E., Stura, E.A., Levitt, D.G., Lee, H.C., Stout, C.D. (1996) Crystal structure of Aplysia ADP-ribosyl cyclase, a homolog of the bifunctional ectozyme CD38. Nature Struct. Biol. 3, 957-964. Citations: 115.
4. Lee, H.C. and Aarhus, R. (1995) A derivative of NADP mobilizes calcium stores insensitive to inositol trisphosphate and cyclic ADP-ribose. J. Biol. Chem. 270, 2152-2157. Citations: 296.
5. Lee, H.C., Aarhus, R., Graeff, R., Gurnack, M.E. and Walseth, T.F. (1994) Cyclic ADP-ribose activation of the ryanodine receptor is mediated by calmodulin. Nature 370, 307-309. Citations: 192.
6. Lee, H.C., Aarhus, R. and Levitt, D. (1994) The crystal structure of cyclic ADP-ribose. Nature Struc. Biol. 1, 143-144. Citations: 113.
7. Howard, M., Grimaldi, J.C., Bazan, J.F., Lund, F.E., Santos-Argumedo, L., Parkhouse, R.M.E., Walseth, T.F. and Lee, H.C. (1993) Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38. Science 262, 1056-1059. Citations: 516.
8. Lee, H.C., Aarhus, R. and Walseth, T.F. (1993) Calcium mobilization by dual receptors during fertilization of sea urchin eggs. Science 261, 352-355. Citations: 262.
9. Galione, A., Lee, H.C. and Busa, W.B. (1991) Ca+2 -induced Ca+2 release in sea urchin egg homogenates and its modulation by cyclic ADP-ribose. Science 253, 1143-1146. Citations: 515.
10. Lee, H.C., Walseth, T.F., Bratt, G.T., Hayes, R.N., and Clapper, D.L. (1989) Structural determination of a cyclic metabolite of NAD+ with intracellular Ca+2 mobilizing activity. J. Biol. Chem. 264, 1608-1615. Citations: 396.
