Cyclic ADP-ribose and related compounds activate sheep skeletal sarcoplasmic reticulum Ca2+ release channel

It has been suggested that adenosine 5'-cyclic-diphosphoribose (cADPR) can activate only nonskeletal isoforms of the ryanodine-sensitive Ca2+ release channel. We now demonstrate that cADPR is an effective activator of sheep skeletal sarcoplasmic reticulum (SR) Ca2+ release channels incorporated into planar phospholipid bilayers in the presence of activating levels of cytosolic Ca2+. In addition, the precursor of cADPR, beta-NAD+, and the metabolite, adenosine diphosphoribose (ADP-ribose), also increase the open probability (Po) of skeletal SR Ca2+ release channels in micromolar concentrations. At low concentrations of cADPR (1 microM), the mechanism for the increase in Po is an increase in the frequency of channel openings with no increase in the duration of the open events. We also show that the effect of cADPR is dependent on luminal [Ca2+]. cADPR has no effect on Po when the luminal [Ca2+] is < 40 microM. However, at millimolar concentrations of luminal Ca2+, cADPR 1 and 10 microM) increases Po in the presence of activating cytosolic Ca2+.