Cyclic ADP ribose is a novel regulator of intracellular Ca2+ oscillations in human bone marrow mesenchymal stem cells.
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.
Affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.Show MeSH
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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  2-aminoethoxydiphenyl borate (50 μM), which is also a blocker of TRPM2 channels , 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.
Affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.