Biochemistry of calcium oscillations

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Abstract

Cytosolic calcium (Ca2+) oscillations are vastly flexible cell signals that convey information regulating numerous cellular processes. The frequency and amplitude of the oscillating signal can be varied infinitely by concerted actions of Ca2+ transporters and Ca2+-binding proteins to encode specific messages that trigger downstream molecular events. High frequency cytosolic Ca2+ oscillations regulate fast responses, such as synaptic transmission and secretion, whereas low frequency oscillations regulate slow processes, such as fertilization and gene transcription. Thus, the cell exploits Ca2+ oscillations as a signalling carrier to transduce vital information that controls its behaviour. Here, we review the underlying biochemical mechanisms responsible for generating and discriminating cytosolic Ca2+ oscillations.

Section snippets

The history of Ca2+ oscillations

The first piece in the calcium (Ca2+) signalling jigsaw puzzle was laid by Sydney Ringer more than a century ago, in 1883, when he discovered that hearts contracted in London tap water but failed to do so in distilled water [1], [2]. Since then thousands of publications have reported Ca2+ signals in various cell types. Cytosolic Ca2+ signals appear in many shapes and can simply be classified as transient, sustained or oscillatory signals. Proteins within the cell have the capacity to decipher

Generation of cytosolic Ca2+ oscillations

The Ca2+-ion is the most widespread cation in the human body and it is uniquely suited for signal transduction [9], [10]. With a low cytosolic resting concentration, ∼10−7 M, and a high extracellular concentration, ∼10−3 M, Ca2+ fluctuations can be generated and detected with only a relatively small increment of Ca2+ added to the cytoplasm. Increase in the cytosolic Ca2+ concentration is driven by the aforementioned large gradient, ∼104, and occurs via influx through integral plasma membrane

Ca2+-increase mechanisms

The oscillatory signal is initiated when the equilibrium in the basal cytosolic Ca2+ level is perturbed somehow. This can occur when the cell senses extracellular stimuli that result in activation of channels that transport Ca2+ into the cytoplasm (Fig. 1). Such channels are located either in the plasma membrane or in the membrane of the endoplasmic/sarcoplasmic reticulum (ER/SR). The nature of the perturbating stimuli is diverse, including membrane voltage alterations, cell-to-cell

Ca2+-decrease mechanisms

As mentioned earlier, a sustained high cytosolic Ca2+ concentration is toxic to the cell. Therefore, the cell has developed mechanisms to clear high levels of cytosolic Ca2+ (Fig. 1). Excess of Ca2+ is mainly pumped into ER/SR stores via the SERCA or removed from the cell across the plasma membrane by Ca2+-ATPases (PMCAs). The Na+/Ca2+-exchanger (NCX) can also transport Ca2+ out of the cell, depending on the ionic gradients across the membrane. Supporting these mechanisms, the mitochondrial

Decoding Ca2+ oscillations

When a Ca2+ signal propagates through the cytoplasm of the cell, several Ca2+ sensors can translate the signal into cellular responses. Amplitude and frequency modulation are then exploited to encode the signal to carry information [33]. A number of proteins have been proposed as decoders of Ca2+ oscillations of which calmodulin (CaM) has been most extensively studied [34]. CaM is a ubiquitously expressed dumbbell-shaped 17 kDa protein with each globular end containing two EF-hands connected by

Biological processes regulated by Ca2+ oscillations

There are numerous reports of biological events activated by cytosolic Ca2+ oscillations. In Table 1 we have listed a few recent examples of biological processes in different cell types that are regulated by cytosolic Ca2+ oscillations. One of the most extensively studied and spectacular event controlled by Ca2+ oscillations is the fertilization of the egg (reviewed in [37], [38]). This discovery can be traced back almost one hundred years when egg activation was observed following injection of

Conclusion

Cytosolic Ca2+ oscillations represent a highly diverse signalling system that regulates numerous processes in all cell types. Work to date has identified many proteins and mechanisms that trigger and modulate this universal signalling pathway. However, much of the molecular basis of the initiation, regulation and discrimination of Ca2+ oscillations remains to be addressed. The rapid development in live cell imaging and bio-probes will surely further our understanding of the nature and

Acknowledgments

We apologize to the many scientists whose work we were not able to credit due to space restrictions. In most cases, reviews have been cited at the expense of the original work. Per Uhlén’s research is supported by the Swedish Research Council (Dnr 2005-6682 and DBRM), the Foundation for Strategic Research (CEDB), Knut and Alice Wallenberg Foundation (CLICK and Research Fellow), The Royal Swedish Academy of Sciences, Fredrik and Ingrid Thuring’s Foundation, Åke Wiberg’s Foundation, Magnus

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