Nitric oxide-induced mobilization of intracellular calcium via the cyclic ADP-ribose signaling pathway.
Cyclic adenosine diphosphate ribose (cADPR) is a potent endogenous calcium-mobilizing agent synthesized from beta-NAD+ by ADP-ribosyl cyclases in sea urchin eggs and in several mammalian cells (Galione, A., and White, A. (1994) Trends Cell Biol. 4, 431 436). Pharmacological studies suggest that cADPR is an endogenous modulator of Ca2+-induced Ca2+ release mediated by ryanodine-sensitive Ca2+ release channels. An unresolved question is whether cADPR can act as a Ca2+-mobilizing intracellular messenger. We show that exogenous application of nitric oxide (NO) mobilizes Ca2+ from intracellular stores in intact sea urchin eggs and that it releases Ca2+ and elevates cADPR levels in egg homogenates. 8-Amino-cADPR, a selective competitive antagonist of cADPR-mediated Ca2+ release, and nicotinamide, an inhibitor of ADP-ribosyl cyclase, inhibit the Ca2+-mobilizing actions of NO, while, heparin, a competitive antagonist of the inositol 1,4,5-trisphosphate receptor, did not affect NO-induced Ca2+ release. Since the Ca2+-mobilizing effects of NO can be mimicked by cGMP, are inhibited by the cGMP-dependent-protein kinase inhibitor, Rp-8-pCPT-cGMPS, and in egg homogenates show a requirement for the guanylyl cyclase substrate, GTP, we suggest a novel action of NO in mobilizing intracellular calcium from microsomal stores via a signaling pathway involving cGMP and cADPR. These results suggest that cADPR has the capacity to act as a Ca2+-mobilizing intracellular messenger.
Willmott
N
N
Department of Pharmacology, Oxford University, Oxford OX1 3QT, United Kingdom.
Sethi
J K
JK
Walseth
T F
TF
Lee
H C
HC
White
A M
AM
Galione
A
A
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006160:Guanosine Triphosphate / Q000494:pharmacology; D007536:Isomerism; D007700:Kinetics; D008322:Mammals; D008954:Models, Biological; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D009243:NAD / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D010063:Ovum / Q000187:drug effects / Q000502:physiology*; D012617:Sea Urchins; D015398:Signal Transduction; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D004791:Enzyme Inhibitors; D013873:Thionucleotides; D009243:NAD; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D009536:Niacinamide; D009569:Nitric Oxide; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D006160:Guanosine Triphosphate; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D006152:Cyclic GMP; D002118:Calcium