Store-operated Ca2+ entry depends on mitochondrial Ca2+ uptake

Abstract

Store-operated Ca 2+ channels, which are activated by the emptying of intracellular Ca 2+ stores, provide one major route for Ca 2+ in¯ux. Under physiological conditions of weak intracellular Ca 2+ buffering, the ubiquitous Ca 2+ releasing messenger InsP 3 usually fails to activate any store-operated Ca 2+ entry unless mitochondria are maintained in an energized state. Mitochondria rapidly take up Ca 2+ that has been released by InsP 3 , enabling stores to empty suf®ciently for store-operated channels to activate. Here, we report a novel role for mitochondria in regulating store-operated channels under physiological conditions. Mitochondrial depolarization suppresses storeoperated Ca 2+ in¯ux independently of how stores are depleted. This role for mitochondria is unrelated to their actions on promoting InsP 3 -sensitive store depletion, can be distinguished from Ca 2+ -dependent inactivation of the store-operated channels and does not involve changes in intracellular ATP, oxidants, cytosolic acidi®cation, nitric oxide or the permeability transition pore, but is suppressed when mitochondrial Ca 2+ uptake is impaired. Our results suggest that mitochondria may have a more fundamental role in regulating store-operated in¯ux and raise the possibility of bidirectional Ca 2+ -dependent crosstalk between mitochondria and store-operated Ca 2+ channels.

Calcineurin Directs the Reciprocal Regulation of Calcium Entry Pathways in Nonexcitable Cells

“…In these, expression of the GFP-c-CAIN construct had no effect on the magnitude of the mean inward current through the SOC channels at Ϫ80 mV with an internal Ca 2ϩ concentration of 400 nM (0.55 Ϯ 0.04 pA/pF, n ϭ 4, versus 0.61 Ϯ 0.02 pA/pF, n ϭ 5, for control cells under the same conditions). Consistent with this, Glitsch et al (28) have reported that currents through the CRAC channels in RBL-1 cells are unaffected by pre-exposure to 5 M CspA. Based on these data, we conclude that calcineurin activity has a specific influence on the ARC channels, and does not affect the magnitude of the current density through SOC channels.…”

Positive and Negative Regulation of High Affinity IgE Receptor Signaling by Src Homology Region 2 Domain-Containing Phosphatase 1

“…To discriminate the intracellular Ca 2ϩ store contributing to the increase of Ca 2ϩ concentration following the stimulation with Ag or TG, it may be required to monitor the Ca 2ϩ concentration in ER as well as in mitochondria simultaneously. Because mitochondria have been shown to reduce Ca 2ϩ -dependent inactivation of CRAC channels by quickly removing the inflowing Ca 2ϩ (66,67), determination of mitochondrial Ca 2ϩ concentration might provide further evidences on the regulation Ca 2ϩ influx thorough CRAC channel.…”

Mitochondrial-Mediated Disregulation of Ca2+ Is a Critical Determinant of Velcade (PS-341/Bortezomib) Cytotoxicity in Myeloma Cell Lines

“…6), leading to caspase activation. Ruthenium compounds would then be protective by blocking mitochondrial loading and CCI activation and the Ca 2+ -dependent signal transduction pathways that initiate cell death (44). The identity of the signal pathways involved in this regulation remains under intense investigation.…”