What is Calmodulin?

Calmodulin is a small protein that binds calcium in cells. It is important in regulating a number of different cellular processes, since calcium signaling is a common way of transmitting signals both between and within cells. An abbreviation for this protein is CaM.

Eukaryotic cells, such as those of humans, are surrounded by a membrane called the plasma membrane, and have structures within them that are membrane-bound, such as the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR). These structures have calcium stores within them, but the cytosol of the cell — the gel-like contents between the membranes — has 10,000 times less calcium than the fluid outside the cells.

The large difference in calcium levels between the cytosol and cell exterior enables the cell to utilize this differential gradient, to introduce calcium as a way to signal responses. There are many proteins that bind calcium, but calmodulin is the most common calcium-modulated protein. Many of the proteins that bind it are unable to respond directly to calcium, and must rely on this calcium-binding protein as a calcium sensor. While many proteins are activated by calcium, others are subject to inhibition. The responses that CaM mediates range from nerve growth and memory to inflammation and metabolism.

A classic example of the role of calmodulin in metabolism is the regulation of the degradation of the body’s glycogen stores for energy. Glycogen is a storage polymer of glucose, and its degradation is initiated by hormones. The binding of these hormones to cellular receptors on the plasma membrane results in a calcium transporter increasing calcium levels within the cell.

As the calcium levels increase in the cytosol, calcium binds calmodulin and changes the protein’s conformation. The calcium-calmodulin complex binds to the calcium transporter, at first increasing, and then decreasing the transport of calcium into the cell. Once the levels of calcium are back to normal, the CaM dissociates from the calcium.

This is an example of the use of a secondary messenger, in which the first signal is a hormone transmitting its extracellular message to the cell surface. The transmission of the signal to the interior of the cell is carried out by a secondary compound, in this case calcium. This two-step process can greatly amplify a cellular response.

There is another level of regulation of glycogen metabolism that represents an additional way in which CaM can exercise control of reactions. It can act upon a calmodulin kinase — a subgroup of kinases specialized to respond to calmodulin. Kinases add a phosphate group to proteins, and the degradation of glycagon is carried out by an enzyme called phosphorylase kinase, that has several sub-units. One of them is a regulatory unit and requires binding by CaM for activity.

Calmodulin is located at many places within the cell, including the ER and SR membranes. It also acts in signaling within the cell. This molecule has similar structures among diverse organisms, indicating that its structure is highly important for its function. The diversity of processes mediated by calmodulin binding is an indicator of the importance of calcium in regulating cellular responses.