Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose (cADPR).
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.
Guse
Andreas H
AH
University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, Cellular Signal Transduction, Hamburg, Germany. guse@uke.uni-hamburg.de
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D051152:Clusterin; D036563:Cyclic ADP-Ribose / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology*; D013329:Structure-Activity Relationship
C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D019837:Ryanodine Receptor Calcium Release Channel; D036563:Cyclic ADP-Ribose; D002118:Calcium