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Article: Modulator and messenger functions of cyclic ADP-ribose in calcium signaling
Title | Modulator and messenger functions of cyclic ADP-ribose in calcium signaling |
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Authors | |
Issue Date | 1996 |
Publisher | The Endocrine Society. The Journal's web site is located at http://rphr.endojournals.org/ |
Citation | Recent Progress In Hormone Research, 1996, v. 51, p. 355-388 How to Cite? |
Abstract | Cyclic ADP-ribose (cADPR), a Ca+2 mobilizing cyclic nucleotide derived from NAD+, is emerging as an endogenous modulator of the Ca+2 induced Ca+2 release (CICR) mechanism in cells. cADPR was discovered because of the prominent delay in the initiation of Ca+2 release by NAD+ in sea urchin egg homogenates, which was due to enzymatic conversion to cADPR. In addition to the egg, an invertebrate cell, amphibian neurons, a variety of mammalian cells and plant vacuoles are found to be responsive to cADPR, indicating its generality. The cyclic structure of cADPR has been determined by X-ray crystallography. A series of analogs has been synthesized, which includes cyclic GDP-ribose, a fluorescent analog, a series of specific antagonists, a photoaffinity label and caged cADPR. The use of these analogs of cADPR has provided definitive evidence for the authenticity of its Ca+2 mobilizing activity and insights for understanding its mechanism and biological functions. Results show that its action requires a soluble protein which is identified as calmodulin. The effect of calmodulin is synergistic with cADPR and both act to sensitize CICR to Ca+2. Together, the Ca+2 sensitivity of CICR can be increased by several orders of magnitude. In addition to being a modulator of CICR, cADPR can also function as a messenger. Activation of its synthetic enzyme can lead to large increases in cellular concentrations of cADPR, which would sensitize CICR to such an extent that even basal levels of cellular Ca+2 are sufficient to trigger further release. This is operationally equivalent to being a Ca+2 messenger. Three types of enzymes are involved in the metabolism of cADPR, a soluble ADP-ribosyl cyclase; a bifunctional ecto-enzyme, CD38, which is also a lymphocyte antigen; and an intracellular enzyme activable by a cGMP-dependent process. The importance of two cysteine residues in the bifunctionality of CD38 has been shown by site-directed mutagenesis. Both ADP-ribosyl cyclase and CD38 can catalyze the exchange of the nicotinamide group in NADP+ with nicotinic acid, leading to the formation of another Ca+2 mobilizing metabolite, nicotinic acid dinucleotide phosphate (NAADP). Pharmacological and desensitization studies show that the NAADP-mechanism is totally independent of the cADPR- and inositol trisphosphate-mechanisms and the Ca+2 stores responsive to NAADP are separable from those sensitive to the other two Ca+2 agonists. Microinjection studies show that all three mechanisms are present and functional in cells. The emerging picture of multiplicity in Ca+2 signaling mechanisms underscores the versatility of Ca+2 in regulating diverse cellular functions. |
Persistent Identifier | http://hdl.handle.net/10722/171626 |
ISSN | |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lee, HC | en_US |
dc.date.accessioned | 2012-10-30T06:16:02Z | - |
dc.date.available | 2012-10-30T06:16:02Z | - |
dc.date.issued | 1996 | en_US |
dc.identifier.citation | Recent Progress In Hormone Research, 1996, v. 51, p. 355-388 | en_US |
dc.identifier.issn | 0079-9963 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/171626 | - |
dc.description.abstract | Cyclic ADP-ribose (cADPR), a Ca+2 mobilizing cyclic nucleotide derived from NAD+, is emerging as an endogenous modulator of the Ca+2 induced Ca+2 release (CICR) mechanism in cells. cADPR was discovered because of the prominent delay in the initiation of Ca+2 release by NAD+ in sea urchin egg homogenates, which was due to enzymatic conversion to cADPR. In addition to the egg, an invertebrate cell, amphibian neurons, a variety of mammalian cells and plant vacuoles are found to be responsive to cADPR, indicating its generality. The cyclic structure of cADPR has been determined by X-ray crystallography. A series of analogs has been synthesized, which includes cyclic GDP-ribose, a fluorescent analog, a series of specific antagonists, a photoaffinity label and caged cADPR. The use of these analogs of cADPR has provided definitive evidence for the authenticity of its Ca+2 mobilizing activity and insights for understanding its mechanism and biological functions. Results show that its action requires a soluble protein which is identified as calmodulin. The effect of calmodulin is synergistic with cADPR and both act to sensitize CICR to Ca+2. Together, the Ca+2 sensitivity of CICR can be increased by several orders of magnitude. In addition to being a modulator of CICR, cADPR can also function as a messenger. Activation of its synthetic enzyme can lead to large increases in cellular concentrations of cADPR, which would sensitize CICR to such an extent that even basal levels of cellular Ca+2 are sufficient to trigger further release. This is operationally equivalent to being a Ca+2 messenger. Three types of enzymes are involved in the metabolism of cADPR, a soluble ADP-ribosyl cyclase; a bifunctional ecto-enzyme, CD38, which is also a lymphocyte antigen; and an intracellular enzyme activable by a cGMP-dependent process. The importance of two cysteine residues in the bifunctionality of CD38 has been shown by site-directed mutagenesis. Both ADP-ribosyl cyclase and CD38 can catalyze the exchange of the nicotinamide group in NADP+ with nicotinic acid, leading to the formation of another Ca+2 mobilizing metabolite, nicotinic acid dinucleotide phosphate (NAADP). Pharmacological and desensitization studies show that the NAADP-mechanism is totally independent of the cADPR- and inositol trisphosphate-mechanisms and the Ca+2 stores responsive to NAADP are separable from those sensitive to the other two Ca+2 agonists. Microinjection studies show that all three mechanisms are present and functional in cells. The emerging picture of multiplicity in Ca+2 signaling mechanisms underscores the versatility of Ca+2 in regulating diverse cellular functions. | en_US |
dc.language | eng | en_US |
dc.publisher | The Endocrine Society. The Journal's web site is located at http://rphr.endojournals.org/ | en_US |
dc.relation.ispartof | Recent Progress in Hormone Research | en_US |
dc.subject.mesh | Adenosine Diphosphate Ribose - Analogs & Derivatives - Antagonists & Inhibitors - Chemistry - Pharmacology - Physiology | en_US |
dc.subject.mesh | Amino Acid Sequence | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Calcium - Metabolism | en_US |
dc.subject.mesh | Calmodulin - Chemistry - Pharmacology | en_US |
dc.subject.mesh | Cyclic Adp-Ribose | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Molecular Sequence Data | en_US |
dc.subject.mesh | Molecular Structure | en_US |
dc.subject.mesh | Plants | en_US |
dc.subject.mesh | Signal Transduction | en_US |
dc.title | Modulator and messenger functions of cyclic ADP-ribose in calcium signaling | 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.pmid | 8701086 | - |
dc.identifier.scopus | eid_2-s2.0-0029706922 | en_US |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-0029706922&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 51 | en_US |
dc.identifier.spage | 355 | en_US |
dc.identifier.epage | 388 | en_US |
dc.identifier.isi | WOS:A1996BJ31P00013 | - |
dc.publisher.place | United States | en_US |
dc.identifier.scopusauthorid | Lee, HC=26642959100 | en_US |
dc.identifier.issnl | 0079-9963 | - |