tailieunhanh - Báo cáo khoa học: Second messenger function and the structure–activity relationship of cyclic adenosine diphosphoribose (cADPR)

Cyclic ADP-ribose (cADPR) is a Ca 2+ mobilizing second messenger found in various cell types, tissues and organisms. Receptor-mediated formation of cADPR may proceed via transmembrane shuttling of the substrate NAD and involvement of the ectoenzyme CD38, or via so far unidentified ADP-ribosyl cyclases located within the cytosol or in internal membranes. cADPR activates intracellular Ca 2+ release via type 2 and 3 ryanodine receptors. | iFEBS Journal MINIREVIEW Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose cADPR Andreas H. Guse University MedicalCenter Hamburg-Eppendorf Center of ExperimentalMedicine Institute of Biochemistry and Molecular Biology I Cellular SignalTransduction Hamburg Germany Correspondence A. H. Guse University MedicalCenter Hamburg-Eppendorf Center of Experimental Medicine Institute of Biochemistry and Molecular Biology I Cellular Signal Transduction Martinistr. 52 20246 Hamburg Germany Fax 49 40 42803 9880 Tel 49 40 42803 2828 E-mail guse@ Received 10 March 2005 accepted 05 July 2005 doi Cyclic ADP-ribose cADPR is a Ca2 mobilizing second messenger found in various cell types tissues and organisms. Receptor-mediated formation of cADPR may proceed via transmembrane shuttling of the substrate NAD and involvement of the ectoenzyme CD38 or via so far unidentified ADP-ribosyl cyclases located within the cytosol or in internal membranes. cADPR activates intracellular Ca2 release via type 2 and 3 ryanodine receptors. The exact molecular mechanism however remains to be elucidated. Possibilities are the direct binding of cADPR to the ryanodine receptor or binding via a separate cADPR binding protein. In addition to Ca2 release cADPR also evokes Ca2 entry. The underlying mechanism s may comprise activation of capacitative Ca2 entry and or activation of the cation channel TRPM2 in conjunction with adenosine diphosphoribose. The development of novel cADPR analogues revealed new insights into the structure-activity relationship. Substitution of either the northern ribose or both the northern and southern ribose resulted in much simpler molecules which still retained significant biological activity. The cyclic ADP-ribose Ca2 signalling pathWay Cyclic ADP-ribose cADPR was discovered in 1987 as a Ca2 mobilizing metabolite of the well-known coenzyme b-nicotinamide adenine dinucleotide NAD .