Modulation of Endoplasmic Reticulum Ca2+ Store Filling by Cyclic ADP-ribose Promotes Inositol Trisphosphate (IP3)-evoked Ca2+ Signals

In addition to its well established function in activating Ca2+ release from the endoplasmic reticulum (ER) through ryanodine receptors (RyR), the second messenger cyclic ADP-ribose (cADPR) also accelerates the activity of SERCA pumps, which sequester Ca2+ into the ER. Here, we demonstrate a potential physiological role for cADPR in modulating cellular Ca2+ signals via changes in ER Ca2+ store content, by imaging Ca2+ liberation through inositol trisphosphate receptors (IP3R) in Xenopus oocytes, which lack RyR. Oocytes were injected with the non-metabolizable analog 3-deaza-cADPR, and cytosolic [Ca2+] was transiently elevated by applying voltage-clamp pulses to induce Ca2+ influx through expressed plasmalemmal nicotinic channels. We observed a subsequent potentiation of global Ca2+ signals evoked by strong photorelease of IP3, and increased numbers of local Ca2+ puffs evoked by weaker photorelease. These effects were not evident with cADPR alone or following cytosolic Ca2+ elevation alone, indicating that they did not arise through direct actions of cADPR or Ca2+ on the IP3R, but likely resulted from enhanced ER store filling. Moreover, the appearance of a new population of puffs with longer latencies, prolonged durations, and attenuated amplitudes suggests that luminal ER Ca2+ may modulate IP3R function, in addition to simply determining the size of the available store and the electrochemical driving force for release.