Lee, Hon Cheung, Ph.D.

FAX 852-2817-1334

• Academy for Excellence in Health Research, Academic Health Center, University of Minnesota, Minneapolis, USA.
• Distinguished McKnight University Professor, University of Minnesota, 1996-2006.
• Honorary degree in Medicine and Surgery, University of Genoa, Italy.
• Editorial Board, Journal of Biological Chemistry, 2003-2008.

• 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.

First Book on cADPR & NAADP

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.

• Guse, A.H. and Lee, H.C. (2008) NAADP: A universal Ca²⁺ trigger. Science Signaling 1, re10. http://stke.sciencemag.org/cgi/reprint/sigtrans;1/44/re10.pdf

• Lee, H.C. (2006) Structure and enzymatic functions of human CD38. Mol. Med. 12, 317-323.

• Lee, H.C. (2005) Nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated calcium signaling. J. Biol. Chem. 280, 33693-33696.

• Lee, H.C. (2003) Calcium signaling: NAADP ascends as a new messenger. Curr. Biol. 13, R186-R188.

• Lee, H.C. (ed.) (2002) Cyclic ADP-ribose and NAADP. Structures, Metabolism and Functions. Dordrecht: Kluwer.

• Lee, H.C. (2001) Physiological functions of cyclic ADP-ribose and NAADP as calcium messengers. Ann. Rev. Pharmacol. Toxicol. 41, 317-345.

• Lee, H.C. (2000) Enzymatic functions and structures of CD38 and homologs. Chem. Immunol. 75, 39-59.

• Lee,H. C. (2000) Multiple calcium stores: Separate but interacting. Science's STKE http://www.stke.org/cgi/content/full/OC_sigtrans;2000/40/pe1

• Lee, H.C. (1997) Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP. Physiol. Rev. 77, 1133-1164.

• 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.

• 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.

• Lee, H.C., Aarhus, R. and Levitt, D. (1994) The crystal structure of cyclic ADP-ribose. Nature Structural Biology 1, 143-144.

• 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.

• 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 Ca²⁺ mobilizing activity. J. Biol. Chem. 264, 1608-1615. 

 Click Here for more publications on Calcium Signaling Mediated by cADPR and NAADP.

 Click Here for more publications on Gastric Acid Secretion and Developmental Biology.

Dr. Lee, Hon Cheung  can be reached at: leehc@hku.hk

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