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 (P-o) of skeletal SR Ca2+ release channels in micromolar concentrations. At low concentrations of cADPR (1 mu M), the mechanism for the increase in P-o 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 P-o when the luminal [Ca2+] is <40 mu M. However, at millimolar concentrations of luminal Ca2+, cADPR (1 and 10 mu M) increases P-o in the presence of activating cytosolic Ca2+.