Hon Cheung Lee, Ph.D.

Cyclic ADP-Ribose (cADPR)

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)

The first book on cyclic ADP-ribose and NAADP is now available from Kluwer Academic Publishers

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. NAADP, a metabolite of NADP, mobilizes the calcium stores through yet another totally independent and novel pathway. Ongoing projects focus on elucidating the mechanisms of the signaling functions of cADPR and NAADP, characterizing their intracellular receptors and delineating the regulation of the enzymatic pathway responsible for their synthesis. X-ray crystallography is used to determine the three dimensional structures of the enzymes involved, and in combination with site-directed mutagenesis, to unravel the catalytic mechanisms of the synthesis and degradation of these messenger molecules.