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- Publisher Website: 10.1016/0167-4889(93)90199-Y
- Scopus: eid_2-s2.0-0027313269
- PMID: 8395888
- WOS: WOS:A1993LX80300001
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Article: Synthesis and characterization of antagonists of cyclic-ADP-ribose-induced Ca2+ release
Title | Synthesis and characterization of antagonists of cyclic-ADP-ribose-induced Ca2+ release |
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Authors | |
Keywords | (S. purpuratus) (Sea urchin egg) 8-Amino-cyclic ADP-ribose Calcium ion mobilization Calcium ion release antagonist cyclic ADP-ribose Microsome |
Issue Date | 1993 |
Publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamcr |
Citation | Biochimica Et Biophysica Acta - Molecular Cell Research, 1993, v. 1178 n. 3, p. 235-242 How to Cite? |
Abstract | Cyclic ADP-ribose (cADPR) is a naturally-occurring metabolite of NAD+ that is as effective as inositol trisphosphate in mobilizing intracellular Ca2+. A series of analogs modified at the 8-position of the adenine group were synthesized for the investigation of the relationship between the structure of the metabolite and its Ca2+-mobilizing activity. Substitution with an amino group at the 8-position of the adenine ring produced an antagonist. The 1H-NMR spectrum of 8-amino-cADPR showed characteristics of that of cADPR and confirmed the replacement of the 8-proton. By itself, 8-amino-cADPR (150 nM) did not induce Ca2+ release from sea-urchin-egg homogenates but totally blocked cADPR (135 nM) from doing so. The effect was reversible, since high concentrations of cADPR could overcome the inhibition. Addition of 8-amino-cADPR to egg homogenates during the cADPR-induced Ca2+ release blocked the release immediately, demonstrating the effectiveness of the antagonist. Measurements of [32P]cADPR binding to its microsomal binding site showed that 8-amino-cADPR was as effective as cADPR itself in competing for the binding site. In addition to blocking cADPR from releasing Ca2+, 8-amino-cADPR also inhibited cADPR from potentiating Ca2+-release induced by either divalent cations or by caffeine. Two other 8-substituted analogs were also synthesized. Both 8-Br- and 8-azido-cADPR were also antagonists, although with less potency than 8-amino-cADPR. These results show that alterations at the 8-position of the adenine group do not inhibit cADPR from binding to its receptor but do eliminate the ability of the metabolite to activate the Ca2+-release mechanism. |
Persistent Identifier | http://hdl.handle.net/10722/171582 |
ISSN | 2023 Impact Factor: 4.6 2023 SCImago Journal Rankings: 1.500 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Walseth, TF | en_US |
dc.contributor.author | Lee, HC | en_US |
dc.date.accessioned | 2012-10-30T06:15:49Z | - |
dc.date.available | 2012-10-30T06:15:49Z | - |
dc.date.issued | 1993 | en_US |
dc.identifier.citation | Biochimica Et Biophysica Acta - Molecular Cell Research, 1993, v. 1178 n. 3, p. 235-242 | en_US |
dc.identifier.issn | 0167-4889 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/171582 | - |
dc.description.abstract | Cyclic ADP-ribose (cADPR) is a naturally-occurring metabolite of NAD+ that is as effective as inositol trisphosphate in mobilizing intracellular Ca2+. A series of analogs modified at the 8-position of the adenine group were synthesized for the investigation of the relationship between the structure of the metabolite and its Ca2+-mobilizing activity. Substitution with an amino group at the 8-position of the adenine ring produced an antagonist. The 1H-NMR spectrum of 8-amino-cADPR showed characteristics of that of cADPR and confirmed the replacement of the 8-proton. By itself, 8-amino-cADPR (150 nM) did not induce Ca2+ release from sea-urchin-egg homogenates but totally blocked cADPR (135 nM) from doing so. The effect was reversible, since high concentrations of cADPR could overcome the inhibition. Addition of 8-amino-cADPR to egg homogenates during the cADPR-induced Ca2+ release blocked the release immediately, demonstrating the effectiveness of the antagonist. Measurements of [32P]cADPR binding to its microsomal binding site showed that 8-amino-cADPR was as effective as cADPR itself in competing for the binding site. In addition to blocking cADPR from releasing Ca2+, 8-amino-cADPR also inhibited cADPR from potentiating Ca2+-release induced by either divalent cations or by caffeine. Two other 8-substituted analogs were also synthesized. Both 8-Br- and 8-azido-cADPR were also antagonists, although with less potency than 8-amino-cADPR. These results show that alterations at the 8-position of the adenine group do not inhibit cADPR from binding to its receptor but do eliminate the ability of the metabolite to activate the Ca2+-release mechanism. | en_US |
dc.language | eng | en_US |
dc.publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamcr | en_US |
dc.relation.ispartof | Biochimica et Biophysica Acta - Molecular Cell Research | en_US |
dc.subject | (S. purpuratus) | - |
dc.subject | (Sea urchin egg) | - |
dc.subject | 8-Amino-cyclic ADP-ribose | - |
dc.subject | Calcium ion mobilization | - |
dc.subject | Calcium ion release antagonist | - |
dc.subject | cyclic ADP-ribose | - |
dc.subject | Microsome | - |
dc.subject.mesh | Adenosine Diphosphate Ribose - Analogs & Derivatives - Antagonists & Inhibitors - Chemical Synthesis - Chemistry | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Binding Sites | en_US |
dc.subject.mesh | Calcium - Metabolism | en_US |
dc.subject.mesh | Calcium Channel Blockers - Chemical Synthesis | en_US |
dc.subject.mesh | Cyclic Adp-Ribose | en_US |
dc.subject.mesh | Cyclic Amp - Analogs & Derivatives - Chemistry - Pharmacology | en_US |
dc.subject.mesh | Magnetic Resonance Spectroscopy | en_US |
dc.subject.mesh | Oocytes - Metabolism | en_US |
dc.subject.mesh | Sea Urchins | en_US |
dc.title | Synthesis and characterization of antagonists of cyclic-ADP-ribose-induced Ca2+ release | en_US |
dc.type | Article | en_US |
dc.identifier.email | Lee, HC:leehc@hku.hk | en_US |
dc.identifier.authority | Lee, HC=rp00545 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1016/0167-4889(93)90199-Y | en_US |
dc.identifier.pmid | 8395888 | - |
dc.identifier.scopus | eid_2-s2.0-0027313269 | en_US |
dc.identifier.volume | 1178 | en_US |
dc.identifier.issue | 3 | en_US |
dc.identifier.spage | 235 | en_US |
dc.identifier.epage | 242 | en_US |
dc.identifier.isi | WOS:A1993LX80300001 | - |
dc.publisher.place | Netherlands | en_US |
dc.identifier.scopusauthorid | Walseth, TF=7005424273 | en_US |
dc.identifier.scopusauthorid | Lee, HC=26642959100 | en_US |
dc.identifier.issnl | 0167-4889 | - |