Biological Membranes - A. N. Ogurtsov 2012

Electrogenesis of Biomembranes
Intracellular Signaling
Intracellular Calcium Oscillations

The interplay between Cell/33.html">Plasma Membrane and internal membrane Ca²⁺ channels, calcium pumps, and calcium-binding Proteins located in both membranes and the Cell Cytoplasm leads to so-called Ca²⁺ oscillations—periodic fluctuations in its cytoplasmic concentration (Figure 143).

In non-excitable Cells, the primary trigger for calcium oscillations is Inositol trisphosphate, which is produced from phosphatidylinositol bisphosphate when phospholipase C is activated by Hormones or growth factors (Figure 139). Inositol trisphosphate is capable of diffusing from The Plasma Membrane, where it is generated, to the membranes of The Endoplasmic reticulum within tens of seconds. The amount and concentration of the resulting IP₃ are high enough to bind to all corresponding receptors, yet Ca²⁺ release occurs only at designated hot spots.

Hot spots refer to transient localized areas within The Cell that emerge, much like bubbles in boiling Water, at various sites on the endoplasmic reticulum membrane due to a high local concentration of Ca²⁺, inositol trisphosphate, or its receptor.

According to current models, the Ca²⁺ released into the cytoplasm at a hot spot diffuses along the reticulum, increasing the sensitivity of the receptor to inositol trisphosphate in its membranes and facilitating channel opening, thereby driving the Propagation of the Ca²⁺ wave front.

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Figure 143 - Dependence of the fluctuation frequency of cytoplasmic Ca²⁺ ion concentration and the magnitude of the biological effect induced by Ca²⁺ ions on hormone concentration

A local rise in Ca²⁺ concentration at this membrane site above the threshold value leads to the inactivation of calcium channels, causing the hot spot to extinguish, while Ca²⁺ diffusion generates new sites of Ca²⁺ release from the reticulum. Calcium pumps also participate in extinguishing hot spots by transporting Ca²⁺ from the Cytosol back into the endoplasmic reticulum or the extracellular space.

In excitable Tissues, the primary influx of Ca²⁺ into the cell occurs via voltage-gated Ca²⁺ channels that are functionally coupled to ryanodine receptors. At the junction between these Two Types of channels, Ca²⁺ release drives the spread of a Ca²⁺ wave of ryanodine receptor activation along the reticulum membranes. Behind the Ca²⁺ wave front, the Ca²⁺ level drops because calcium is already depleted in that region of the reticulum, meaning Ca²⁺ no longer exits through the channels; conversely, calcium pumps actively clear Ca²⁺ from the cytoplasm. In excitable cells, the frequency of Ca²⁺ oscillations can be enhanced by IP₃, cyclic ADP-ribose, or caffeine.

In many cell types, the calcium oscillation wave propagates outward from the Cell Nucleus and can take the form of expanding spheres or complex spirals.

In certain tissues (such as The Heart and Brain), calcium oscillations originating in a single cell can stimulate Ca²⁺ oscillations in neighboring cells at the exact same frequency as in the initiating cell.

Apparently, in these tissues, the Ca²⁺ wave can propagate through intercellular Gap Junctions (see Section 16.1), which possess high ionic conductance.

Within a single cell's cytoplasm, hormones and growth factors have virtually no effect on the amplitude of the Ca²⁺ concentration increase, but they do increase the frequency of its fluctuations (Figure 143). Typically, cytoplasmic Ca²⁺ levels range from 10 to 5·10^-7 M, with frequencies ranging from one oscillation per minute to several oscillations per second.

The Ca²⁺-dependent effects of hormones and growth factors are directly proportional to the frequency of cytoplasmic Ca²⁺ fluctuations (Figure 143). This can be explained by the fact that higher oscillation frequencies increase the probability of calcium-binding proteins becoming saturated with calcium.

While dissociation of Ca²⁺ from high-affinity sites on calcium-binding proteins takes minutes, cytoplasmic Ca²⁺ oscillates much faster; consequently, calcium-binding proteins perceive this frequency information and—much like AC-to-DC converters—translate it into a slowly developing metabolic, morphological, or functional shift in the cell over the course of minutes or hours.

Calcium-binding proteins may contain multiple Ca²⁺-binding sites that exhibit positive cooperativity. Upon Ca²⁺ binding, the Protein Structure may feature an increased number of $\alpha$-helices, frequently exposing functional groups On the surface of the protein globule that mediate the interaction between the calcium-binding protein and downstream effector proteins. In this manner, Ca²⁺ induces Protein-Protein Interactions that alter their activity or cellular localization.

Ca²⁺ activates numerous catabolic processes (Glycolysis, lipolysis, proteolysis) and also stimulates Protein Synthesis, Muscle contraction and non-muscle motility, exocytosis, ion transport, and neurotransmitter secretion.