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Cyclic ADP ribose is a novel regulator of intracellular Ca2+ oscillations in human bone marrow mesenchymal stem cells.

Tao R, Sun HY, Lau CP, Tse HF, Lee HC, Li GR - J. Cell. Mol. Med. (2011)

Bottom Line: However, cADPR had no effect on adipogenesis or osteogenesis in human MSCs.Our results indicate that cADPR is a novel regulator of Ca(2+) (i) oscillations in human MSCs.It permeates the cell membrane through the nucleoside transporters and increases Ca(2+) oscillation via activation of the TRPM2 channel, resulting in enhanced phosphorylation of ERK1/2 and, thereby, stimulation of human MSC proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

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Effects of cADPR on spontaneous Ca2+i oscillations. (A) Cyclic ADP ribose did not initiate Ca2+i transient or Ca2+i oscillations in the cell without spontaneous Ca2+i oscillations. (B and C) Cyclic ADP ribose increased frequency of Ca2+i oscillations at 10 and 50 μM. (D) 8-Br-cADPR prevented the effect of cADPR on Ca2+i oscillations. (E) Ryanodine (30 μM) did not antagonize the cADPR effect. (F) IP3Rs blocker 2-APB (50 μM) blocked Ca2+i oscillations and prevented the cADPR effect. (G) Mean values of Ca2+i oscillation frequencies in the absence or presence of cADPR under conditions of the effects of 10 μM (n = 20), 50 μM (n = 36), 100 μM 8-Br-cADPR plus 50 μM cADPR (n = 23) and 30 μM ryanodine plus 50 μM cADPR (n = 21) on frequency of Ca2+i oscillations. *P < 0.05 versus before cADPR, #P < 0.05 versus 10 μM cADPR.
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fig02: Effects of cADPR on spontaneous Ca2+i oscillations. (A) Cyclic ADP ribose did not initiate Ca2+i transient or Ca2+i oscillations in the cell without spontaneous Ca2+i oscillations. (B and C) Cyclic ADP ribose increased frequency of Ca2+i oscillations at 10 and 50 μM. (D) 8-Br-cADPR prevented the effect of cADPR on Ca2+i oscillations. (E) Ryanodine (30 μM) did not antagonize the cADPR effect. (F) IP3Rs blocker 2-APB (50 μM) blocked Ca2+i oscillations and prevented the cADPR effect. (G) Mean values of Ca2+i oscillation frequencies in the absence or presence of cADPR under conditions of the effects of 10 μM (n = 20), 50 μM (n = 36), 100 μM 8-Br-cADPR plus 50 μM cADPR (n = 23) and 30 μM ryanodine plus 50 μM cADPR (n = 21) on frequency of Ca2+i oscillations. *P < 0.05 versus before cADPR, #P < 0.05 versus 10 μM cADPR.

Mentions: Figure 2A shows that the addition of cADPR (50 μM) to the bath solution did not induce Ca2+ changes in the cells exhibiting no spontaneous Ca2+i oscillations (n = 16). However, cADPR (10 and 50 μM) remarkably enhanced the Ca2+i oscillation frequency in cells with spontaneous Ca2+i oscillations (Fig. 2B and C). 8-Br-cADPR (100 μM), a specific antagonist of cADPR, had no effect on the spontaneous Ca2+i oscillations, but prevented the enhancing effect of cADPR on the oscillation frequency (Fig. 2D). Interestingly, the enhancement of the Ca2+i oscillation frequency by cADPR was not affected by 30 μM ryanodine (Fig. 2E). The IP3Rs blocker [8] 2-aminoethoxydiphenyl borate (50 μM), which is also a blocker of TRPM2 channels [35], fully suppressed the Ca2+i oscillations and antagonized the enhancement on Ca2+i oscillation frequency by cADPR (Fig. 2F). Therefore, the inhibitory effect could be related at least in part to its action on the TRPM2 channels. Indeed, as it will be described in detail below, the TRPM2 channel is likely the target of cADPR instead of the RyRs.


Cyclic ADP ribose is a novel regulator of intracellular Ca2+ oscillations in human bone marrow mesenchymal stem cells.

Tao R, Sun HY, Lau CP, Tse HF, Lee HC, Li GR - J. Cell. Mol. Med. (2011)

Effects of cADPR on spontaneous Ca2+i oscillations. (A) Cyclic ADP ribose did not initiate Ca2+i transient or Ca2+i oscillations in the cell without spontaneous Ca2+i oscillations. (B and C) Cyclic ADP ribose increased frequency of Ca2+i oscillations at 10 and 50 μM. (D) 8-Br-cADPR prevented the effect of cADPR on Ca2+i oscillations. (E) Ryanodine (30 μM) did not antagonize the cADPR effect. (F) IP3Rs blocker 2-APB (50 μM) blocked Ca2+i oscillations and prevented the cADPR effect. (G) Mean values of Ca2+i oscillation frequencies in the absence or presence of cADPR under conditions of the effects of 10 μM (n = 20), 50 μM (n = 36), 100 μM 8-Br-cADPR plus 50 μM cADPR (n = 23) and 30 μM ryanodine plus 50 μM cADPR (n = 21) on frequency of Ca2+i oscillations. *P < 0.05 versus before cADPR, #P < 0.05 versus 10 μM cADPR.
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fig02: Effects of cADPR on spontaneous Ca2+i oscillations. (A) Cyclic ADP ribose did not initiate Ca2+i transient or Ca2+i oscillations in the cell without spontaneous Ca2+i oscillations. (B and C) Cyclic ADP ribose increased frequency of Ca2+i oscillations at 10 and 50 μM. (D) 8-Br-cADPR prevented the effect of cADPR on Ca2+i oscillations. (E) Ryanodine (30 μM) did not antagonize the cADPR effect. (F) IP3Rs blocker 2-APB (50 μM) blocked Ca2+i oscillations and prevented the cADPR effect. (G) Mean values of Ca2+i oscillation frequencies in the absence or presence of cADPR under conditions of the effects of 10 μM (n = 20), 50 μM (n = 36), 100 μM 8-Br-cADPR plus 50 μM cADPR (n = 23) and 30 μM ryanodine plus 50 μM cADPR (n = 21) on frequency of Ca2+i oscillations. *P < 0.05 versus before cADPR, #P < 0.05 versus 10 μM cADPR.
Mentions: Figure 2A shows that the addition of cADPR (50 μM) to the bath solution did not induce Ca2+ changes in the cells exhibiting no spontaneous Ca2+i oscillations (n = 16). However, cADPR (10 and 50 μM) remarkably enhanced the Ca2+i oscillation frequency in cells with spontaneous Ca2+i oscillations (Fig. 2B and C). 8-Br-cADPR (100 μM), a specific antagonist of cADPR, had no effect on the spontaneous Ca2+i oscillations, but prevented the enhancing effect of cADPR on the oscillation frequency (Fig. 2D). Interestingly, the enhancement of the Ca2+i oscillation frequency by cADPR was not affected by 30 μM ryanodine (Fig. 2E). The IP3Rs blocker [8] 2-aminoethoxydiphenyl borate (50 μM), which is also a blocker of TRPM2 channels [35], fully suppressed the Ca2+i oscillations and antagonized the enhancement on Ca2+i oscillation frequency by cADPR (Fig. 2F). Therefore, the inhibitory effect could be related at least in part to its action on the TRPM2 channels. Indeed, as it will be described in detail below, the TRPM2 channel is likely the target of cADPR instead of the RyRs.

Bottom Line: However, cADPR had no effect on adipogenesis or osteogenesis in human MSCs.Our results indicate that cADPR is a novel regulator of Ca(2+) (i) oscillations in human MSCs.It permeates the cell membrane through the nucleoside transporters and increases Ca(2+) oscillation via activation of the TRPM2 channel, resulting in enhanced phosphorylation of ERK1/2 and, thereby, stimulation of human MSC proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Show MeSH
Related in: MedlinePlus