Modulation of store-operated Ca2+ entry by cyclic-ADP-ribose

Abstract

Store-operated Ca 2+ entry plays an important role in Ca 2+ homeostasis in cells but the mechanisms of control of these channels are not completely understood. We describe an investigation of the role of the CD38-cyclic-ADP-ribose (cADPR)-ryanodine-channel (RyR) signaling pathway in store-operated Ca 2+ entry in human smooth muscle. We observed that human myometrial cells have a functional storeoperated Ca 2+ entry mechanism. Furthermore, we observed the presence of transient receptor potential 1, 3, 4, 5, and 6 ion channels in human myometrial cells. Store-operated Ca 2+ transient was inhibited by at least 50-70% by several inhibitors of the RyR, including ryanodine (10 µM), dantrolene (10 µM), and ruthenium red (10 µM). Furthermore, the cell permeable inhibitor of the cADPR-system, 8-Br-cADPR (100 µM), is a potent inhibitor of the store-operated entry, decreasing the store operated entry by 80%. Pre-incubation of cells with 100 µM cADPR and the hydrolysis-resistant cADPR analog 3-deaza-cADPR (50 µM), but not with ADP-ribose (ADPR) leads to a 1.6-fold increase in the store-operated Ca 2+ transient. In addition, we observed that nicotinamide (1-10 mM), an inhibitor of cADPR synthesis, also leads to inhibition of the store-operated Ca 2+ transient by 50-80%. Finally, we observed that the transient receptor potential channels, RyR, and CD38 can be co-immunoprecipitated, indicating that they interact in vivo. Our observations clearly implicate the CD38-cADPR-ryanodine signaling pathway in the regulation of storeoperated Ca 2+ entry in human smooth muscle cells.

Endothelium- and smooth muscle-dependent vasodilator effects of Citrus aurantium L. var. amara: Focus on Ca2+ modulation

“…This interpretation would be consistent with a previous study showing that linalool, the major component of neroli, evoked intracellular Ca 2+ release in human cells [20]. However, since ruthenium red decreases store-operated Ca 2+ entry [21], it is more likely that neroli inhibits a RyR-dependent, storeoperated Ca 2+ entry pathway rather than directly affecting intracellular Ca 2+ release. Neroli essential oil and its main components, commonly used in foods and as a natural complement to standard therapies, are known to exert relaxation effects [16].…”

Conformation of ryanodine receptor-2 gates store-operated calcium entry in rat pulmonary arterial myocytes

“…5 -8 This is also consistent with the observations that the endogenous RyR agonist cyclic-ADP-ribose (cADPR) activated Ca 2+ influx in human myometrial cells and in RyR1 and TRPC3 coexpressing HEK293 cells; and the cADPR inhibitor 8-Br-cADPR attenuated Ca 2+ influx induced by endothelin-1 in myometrial cells. 7,15 However, it is in contrast to the early study in canine PASMCs that depletion of both InsP 3 R-and RyR-sensitive Ca 2+ stores are required to elicit SOCE. 30,31 Since vasoactive agonist was not used in our experiments and inhibition of InsP 3 R with xestospongin C did not affect RyRmediated Ca 2+ entry, our results clearly show that stimulation of RyR can independently activate SOCE in rat PASMCs.…”

Regulation of store-operated Ca2+entry by CD38 in human airway smooth muscle

“…These data are consistent with studies in other tissues showing CD38 modulation of influx via different channels, although not necessarily SOCE. Indeed, only one other study in myometrial smooth muscle has demonstrated CD38 modulation of SOCE (54).…”