Calcium as a second messenger

Ca2+ acts as a signal molecule within the cell. This works by tightly limiting the time and space when Ca2+ is free (and thus active). Therefore, the concentration of free Ca2+ within the cell is usually very low; it is stored within organelles, usually the endoplasmic reticulum (sarcoplasmic reticulum in muscle cells), where it is bound to molecules like calreticulin.

Activation of Ca2+

To become active, Ca2+ has to be released from the endoplasmic reticulum into the cytosol. There are two combined receptor/ion channel proteins that perform the task of controlled transport of Ca2+:
- The InsP3-receptor will transport Ca2+ upon interaction with inositol triphosphate (thus the name) on its cytosolic side. It consists of four identical subunits.
- The ryanodine receptor is named after the plant alkaloid ryanodine. It is similar to the InsP3 receptor and stimulated to transport Ca2+ into the cytosol by recognizing Ca2+ on its cytosolic side, thus establishing a feedback mechanism; a small amount of Ca2+ in the cytosol near the receptor will cause it to release even more Ca2+. It is especially important in neurons and muscle cells. In heart and pancreas cells, another second messenger (cyclic ADP ribose) takes part in the receptor activation.

The localized and time-limited activity of Ca2+ in the cytosol is also called a Ca2+ wave. The building of the wave is done by:
- the feedback mechanism of the ryanodine receptor and
- the activation of phospholipase C by Ca2+, which leads to the production of inositol triphosphate, which in turn activates the InsP3 receptor.

Function of Ca2+

Ca2+ is used in a multitude of processes, among them muscle contraction, release of neurotransmitter from nerve endings, vision in retina cells, proliferation, secretion, cytoskeleton management, cell migration, gene expression and metabolism. The three main pathways that lead to Ca2+ activation are :
1. G protein regulated pathways
2. Pathways regulated by receptor-tyrosine kinases
3. Ligand- or current-regulated ion channels

There are two different ways in which Ca2+ can regulate proteins:
1. A direct recognition of Ca2+ by the protein.
2. Binding of Ca2+ in the active site of an enzyme

One of the best studied interactions of Ca2+ with a protein is the regulation of calmodulin by Ca2+. Calmodulin itself can regulate other proteins, or be part of a larger protein (for example, phosphorylase kinase). The Ca2+/calmodulin complex plays an important role in proliferation, mitosis and neural signal transduction.


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