negative regulation of release of sequestered calcium ion into cytosol

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of the release into the cytosolic compartment of calcium ions sequestered in the endoplasmic reticulum or mitochondria. [GOC:ai]

Negative regulation of release of sequestered calcium ion into cytosol is a crucial cellular process that fine-tunes calcium signaling by controlling the release of calcium ions (Ca2+) from intracellular stores. Calcium ions are vital second messengers involved in a wide range of cellular functions, including muscle contraction, neurotransmitter release, enzyme activation, and gene expression. However, uncontrolled release of calcium can lead to cellular dysfunction and damage. Therefore, mechanisms exist to tightly regulate the release of Ca2+ from intracellular stores, specifically the endoplasmic reticulum (ER), where it is sequestered. This process is referred to as negative regulation of release of sequestered calcium ion into cytosol.

Here's a detailed description of the biological process:

1. **Calcium Sequestration in the ER:** The ER is a major intracellular calcium store. Specialized calcium pumps, known as SERCA (sarco/endoplasmic reticulum Ca2+-ATPase), actively transport Ca2+ from the cytosol into the ER lumen, against its concentration gradient. This process requires energy, provided by ATP hydrolysis. The ER lumen maintains a high concentration of Ca2+ compared to the cytosol.

2. **Calcium Release Channels:** The ER membrane contains various calcium release channels that facilitate the release of Ca2+ back into the cytosol. The most prominent channel is the inositol trisphosphate receptor (IP3R), a ligand-gated calcium channel activated by IP3. Another important channel is the ryanodine receptor (RyR), a voltage-gated calcium channel activated by changes in membrane potential.

3. **Negative Regulation Mechanisms:**
* **IP3R and RyR Modulation:**
* **IP3 Levels:** The activation of IP3R is tightly regulated by IP3 levels. The production of IP3 is triggered by various signaling pathways, including the activation of G protein-coupled receptors (GPCRs) and tyrosine kinase receptors. Once IP3 is generated, it binds to IP3R, causing its conformational change and opening of the channel, allowing Ca2+ release. However, IP3 degradation or depletion can deactivate IP3R, shutting down the channel and limiting Ca2+ release.
* **Ca2+ Feedback:** Both IP3R and RyR are subject to calcium-induced calcium release (CICR). When a small amount of Ca2+ is released from the ER, it can further activate the channels, leading to a larger Ca2+ release. However, this positive feedback loop is also subject to negative regulation. As Ca2+ concentration in the cytosol rises, it can bind to specific sites on the channels, leading to their inactivation. This mechanism prevents excessive Ca2+ release and protects cells from calcium overload.
* **Calcium Buffering:** The cytosol contains various calcium-binding proteins, such as calbindin and parvalbumin, which act as calcium buffers. These proteins bind to free Ca2+ in the cytosol, reducing its concentration and minimizing its signaling impact. This buffering action also helps to prevent calcium overload and maintain appropriate Ca2+ levels for specific signaling pathways.
* **Calcium Reuptake:** SERCA pumps continuously remove Ca2+ from the cytosol and sequester it back into the ER. This process helps to maintain a low cytosolic Ca2+ concentration and limits the duration of calcium signals.

4. **Significance of Negative Regulation:**
* **Precise Calcium Signaling:** The negative regulation of Ca2+ release ensures that Ca2+ signals are precisely controlled in terms of amplitude, duration, and spatial distribution. This precision is essential for the specificity and effectiveness of calcium signaling in various cellular processes.
* **Prevention of Calcium Overload:** Excessive Ca2+ release can overwhelm cellular mechanisms and trigger apoptosis (programmed cell death) or other detrimental effects. Negative regulation prevents this by limiting the extent of Ca2+ release.
* **Cellular Homeostasis:** The tight regulation of calcium release is crucial for maintaining cellular homeostasis. It ensures that Ca2+ levels are kept within a narrow range, allowing cells to function properly.

In summary, negative regulation of release of sequestered calcium ion into cytosol is a complex process that involves multiple mechanisms to tightly control the release of Ca2+ from the ER. These mechanisms are essential for precise calcium signaling, prevention of calcium overload, and maintenance of cellular homeostasis.'
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Proteins (3)

Compounds (12)