2'-Phospho-cyclic ADP-ribose, a calcium-mobilizing agent derived from NADP.
Cyclic adenosine diphosphoribose (cADPR), a metabolite of NAD, appears to modulate changes in intracellular free Ca2+ levels by activation of ryanodine-sensitive Ca2+ channels. We report here that an ADPR cyclase purified from Aplysia californica readily catalyzes the conversion of NADP to 2'-phospho-cyclic adenosine diphosphoribose (2'-P-cADPR), cyclized at N-1 of the adenine moiety. An enzyme from canine spleen previously shown to contain NAD glycohydrolase, ADPR cyclase, and cADPR hydrolase activities also utilized NADP and 2'-P-cADPR as substrates. The apparent Km value for NADP was 1.6 microM compared with 9.9 microM for NAD, and the Vmax with NADP was twice that with NAD, indicating that 2'-P-cADPR is a likely metabolite in mammalian cells. 2'-P-cADPR was as active as cADPR in eliciting Ca2+ release from rat brain microsomes, but was unable to elicit Ca2+ release following conversion to 2'-P-ADPR by the action of canine spleen NAD glycohydrolase. 2'-P-cADPR and 1-D-myo-inositol 1,4,5-trisphosphate (IP3) appear to act by distinct mechanisms as microsomes desensitized to IP3 still released Ca2+ in response to 2'-P-cADPR and vice versa. Also, inhibition of IP3-induced Ca2+ release by heparin had no effect on release by 2'-P-cADPR. Both 2'-P-cADPR and cADPR appear to act by a similar mechanism based on similar kinetics of Ca2+ release, similar dose-response curves, cross-desensitization, and partial inhibition of release by procaine. The results of this study suggest that 2'-P-cADPR may function as a new component of Ca2+ signaling and a possible link between NADP metabolism and Ca2+ homeostasis.
Vu
C Q
CQ
Division of Medicinal Chemistry and Pharmaceutics, College of Pharmacy and the Lucille P. Markey Cancer Center, University of Kentucky, Lexington, 40536-0082, USA.
Lu
P J
PJ
Chen
C S
CS
Jacobson
M K
MK
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D001048:Aplysia / Q000201:enzymology; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives*; D004285:Dogs; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007700:Kinetics; D008190:Lyases / Q000378:metabolism*; D008562:Membrane Glycoproteins; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D009124:Muscle Proteins / Q000187:drug effects / Q000502:physiology; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D009244:NAD+ Nucleosidase / Q000378:metabolism*; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism*; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel; D013056:Spectrophotometry, Ultraviolet; D013154:Spleen / Q000201:enzymology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015220:Calcium Channels; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C098663:cyclic ADP-ribose 2'-phosphate; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D009249:NADP; D015544:Inositol 1,4,5-Trisphosphate; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D008190:Lyases; D002118:Calcium