2'phospho-cyclic adp-rtbose, A new calcium mobilizing agent derived from nadp

C. O. Vu, Pei-Jung Lu, C. S. Chen, M. K. Jacobson

Research output: Contribution to journalArticle

Abstract

The metabolism of cyclic ADP-ribose (cADPR), a potential second messenger of Ca2 signaling, is mediated by NAD glycohydrolases (NADases) containing ADPR cyclase and cADPR hydrolase activities. Many NADases use both NAD and NADP as substrates, raising the possibility that they may also catalyze the formation of a cyclic nucleotide from NADP. We report here that Aplysia ADPR cyclase, an enzyme with strong sequence homology to several mammalian NADases, efficiently catalyzes the conversion of NADP to 2'phospho-cyclic ADP-ribose (2'PcADPR). The structure of 2'P-cADPR was determined by spectral and enzymatic methods. A canine spleen NADase that synthesizes cADPR from NAD and hydrolyzes it to ADPR also utilizes NADP and 2'P-cADPR as substrates. The enzyme showed a kinetic preference for NADP over NAD with a ratio of kcal/Km for NADP 12-fold greater than that for NAD, suggesting that the conversion of NADP to 2'P-cADPR is likely to occur in mammalian systems. Similar to cADPR, 2'P-cADPR was active in eliciting Ca2+ release from rat brain microsomes. The mechanism of Ca2 release by 2'P-cADPR was different from that of inositol 1,4,5-trisphosphate (IPs) as microsomes desensitized to one agent still responded to the other. Also, the action of IPj was virtually abolished by the presence of heparin while the activity of 2'P-cADPR was unaffected. Both 2'P-cADPR and cADPR appeared to act by a similar mechanism based on similar kinetics of Ca2 release, similar dose-response curves, cross-desensitization of Ca2 release, and partial inhibition by procaine. The results of this study indicate that 2'P-cADPR may function as a link between NADP metabolism and Ca2 homeostasis. Supported in part by NIH grant CA43894.

Original languageEnglish
JournalFASEB Journal
Volume10
Issue number3
Publication statusPublished - 1996 Dec 1

Fingerprint

Cyclic ADP-Ribose
ribose
Calcium
NADP
calcium
NAD+ Nucleosidase
ADP-ribosyl Cyclase
NAD
glycosidases
Microsomes
Metabolism
microsomes
Aplysia
Procaine
Kinetics
Inositol 1,4,5-Trisphosphate
2'P-ADP
Organized Financing
procaine
Cyclic Nucleotides

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Vu, C. O. ; Lu, Pei-Jung ; Chen, C. S. ; Jacobson, M. K. / 2'phospho-cyclic adp-rtbose, A new calcium mobilizing agent derived from nadp. In: FASEB Journal. 1996 ; Vol. 10, No. 3.
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abstract = "The metabolism of cyclic ADP-ribose (cADPR), a potential second messenger of Ca2 signaling, is mediated by NAD glycohydrolases (NADases) containing ADPR cyclase and cADPR hydrolase activities. Many NADases use both NAD and NADP as substrates, raising the possibility that they may also catalyze the formation of a cyclic nucleotide from NADP. We report here that Aplysia ADPR cyclase, an enzyme with strong sequence homology to several mammalian NADases, efficiently catalyzes the conversion of NADP to 2'phospho-cyclic ADP-ribose (2'PcADPR). The structure of 2'P-cADPR was determined by spectral and enzymatic methods. A canine spleen NADase that synthesizes cADPR from NAD and hydrolyzes it to ADPR also utilizes NADP and 2'P-cADPR as substrates. The enzyme showed a kinetic preference for NADP over NAD with a ratio of kcal/Km for NADP 12-fold greater than that for NAD, suggesting that the conversion of NADP to 2'P-cADPR is likely to occur in mammalian systems. Similar to cADPR, 2'P-cADPR was active in eliciting Ca2+ release from rat brain microsomes. The mechanism of Ca2 release by 2'P-cADPR was different from that of inositol 1,4,5-trisphosphate (IPs) as microsomes desensitized to one agent still responded to the other. Also, the action of IPj was virtually abolished by the presence of heparin while the activity of 2'P-cADPR was unaffected. Both 2'P-cADPR and cADPR appeared to act by a similar mechanism based on similar kinetics of Ca2 release, similar dose-response curves, cross-desensitization of Ca2 release, and partial inhibition by procaine. The results of this study indicate that 2'P-cADPR may function as a link between NADP metabolism and Ca2 homeostasis. Supported in part by NIH grant CA43894.",
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2'phospho-cyclic adp-rtbose, A new calcium mobilizing agent derived from nadp. / Vu, C. O.; Lu, Pei-Jung; Chen, C. S.; Jacobson, M. K.

In: FASEB Journal, Vol. 10, No. 3, 01.12.1996.

Research output: Contribution to journalArticle

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