Cyclic adenosine diphosphoribose (cADPR), a metabolite of NAD, appears to modulate changes in intracellular free Ca levels by activation of ryanodine-sensitive Ca 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 K value for NADP was 1.6 µM compared with 9.9 µM for NAD, and the V 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 Ca release from rat brain microsomes, but was unable to elicit Ca 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 (IP) appear to act by distinct mechanisms as microsomes desensitized to IP still released Ca in response to 2`-P-cADPR and vice versa. Also, inhibition of IP-induced Ca 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 Ca 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 Ca signaling and a possible link between NADP metabolism and Ca homeostasis.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				R. Laporte, A. Hui, and I. Laher Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle Pharmacol. Rev., December 1, 2004; 56(4): 439 - 513. [Abstract] [Full Text] [PDF]

				J-P Mothet, P Fossier, F-M Meunier, J Stinnakre, L Tauc, and G Baux Cyclic ADP-ribose and calcium-induced calcium release regulate neurotransmitter release at a cholinergic synapse of Aplysia J. Physiol., March 1, 1998; 507(2): 405 - 414. [Abstract] [Full Text] [PDF]

				H. Higashida, S. Yokoyama, M. Hashii, M. Taketo, M. Higashida, T. Takayasu, T. Ohshima, S. Takasawa, H. Okamoto, and M. Noda Muscarinic Receptor-mediated Dual Regulation of ADP-ribosyl Cyclase in NG108-15 Neuronal Cell Membranes J. Biol. Chem., December 12, 1997; 272(50): 31272 - 31277. [Abstract] [Full Text] [PDF]

				A. De Flora, L. Guida, L. Franco, E. Zocchi, S. Bruzzone, U. Benatti, G. Damonte, and H. C. Lee CD38 and ADP-ribosyl Cyclase Catalyze the Synthesis of a Dimeric ADP-ribose That Potentiates the Calcium-mobilizing Activity of Cyclic ADP-ribose J. Biol. Chem., May 16, 1997; 272(20): 12945 - 12951. [Abstract] [Full Text] [PDF]