Abstract
Ca 2+ oscillations, a widespread mode of cell signaling, were reported in non-excitable cells for the first time more than 25 years ago. Their fundamental mechanism, based on the periodic Ca 2+ exchange between the endoplasmic reticulum and the cytoplasm, has been well characterized. However, how the kinetics of cytosolic Ca 2+ changes are related to the extent of a physiological response remains poorly understood. Here, we review data suggesting that the downstream targets of Ca 2+ are controlled not only by the frequency of Ca 2+ oscillations but also by the detailed characteristics of the oscillations, such as their duration, shape, or baseline level. Involvement of non-endoplasmic reticulum Ca 2+ stores, mainly mitochondria and the extracellular medium, participates in this fine tuning of Ca 2+ oscillations. The main characteristics of the Ca 2+ exchange fluxes with these compartments are also reviewed.
Highlights
Most of the time, the hormone-induced Ca2+ increases that activate a variety of essential intracellular processes take the form of Ca2+ oscillations
It is clear that in many cases the existence of Ca2+ oscillations does not provide an ON/OFF signal for the Ca2+-mediated response to the stimulus nor is the extent of the response only determined by the frequency of the oscillations
Ca2+ exchanges with mitochondria and storeoperated calcium entry (SOCE) play an important role in fine tuning cytosolic Ca2+ oscillations
Summary
The hormone-induced Ca2+ increases that activate a variety of essential intracellular processes take the form of Ca2+ oscillations. In addition to its effect on the frequency of the oscillations, the MCU controls the width of the spikes and the sustainability of the oscillations, as knockingdown the MCU broadens Ca2+ oscillations and accelerates the rundown of the oscillations in rat basophilic leukemia (RBL)-1 cells (Figure 3) Such rundown suppresses gene expression in response to leukotriene receptor activation[37]. The origin and the physiological significance of this unusual behavior remains unknown, it might be related to the inactivation of SOCEmediated Ca2+ entry by cytosolic Ca2+ itself, a process that has long been thought to be mediated by calmodulin[56] but was recently suggested to be due to a calmodulin-independent conformational change within the pore allowed by two specific Orai residues, Y80 and W7657,58 This Ca2+-induced inactivation (CDI) of SOCE allows for a modulation of Ca2+ entry depending on the level of cytosolic Ca2+, shaping the oscillations. Female mice lacking Orai[1] are fertile[65], while male mice are sterile due to severe defects in spermatogenesis[66]
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