Second Messengers

If you’ve ever had an urge to run away from a growling dog, you’ve activated your body’s fight or flight instinct. The “fight or flight” mechanism is our bodies’ way of preparing for situations of heightened stress. This mechanism is triggered by the release of the hormone epinephrine (also known as adrenaline) by the adrenal glands.

When epinephrine binds to cell-surface receptors, it stimulates the production of the second messenger cAMP which then increases the production of cortisol. When released into the bloodstream, cortisol triggers various cellular responses in various parts of the body, resulting in higher blood pressure and blood sugar levels as well as the suppression of the immune system.

So what exactly is a second messenger? Here, we will define what a second messenger is, describe its function in signal transduction, and cite examples of second messengers.

Second messenger systems in signal transduction

Cell signaling is the process in which a signaling molecule called ligand binds to a receptor protein in or on the target cell, triggering a specific cellular response such as cell growth or cell death.

Small and hydrophobic or nonpolar ligands including steroid hormones like testosterone and progesterone can permeate the hydrophobic interior of the plasma membrane so they can bind to intracellular receptors (or internal receptors) in the cytoplasm and directly influence DNA.

On the other hand, hydrophilic or polar ligands such as amino acid-derived hormones cannot pass through the plasma membrane so they need to transmit the signal to other receptors or messengers through a process called signal transduction.

The network through which a signal is transmitted via the sequential activation (or deactivation) of receptor proteins or second messengers is called the signal transduction pathway.

Second messenger definition in biology

In a signal transduction pathway, second messengers are small, non-protein molecules or ions that transmit a signal that has been generated when the ligand binds to the cell-surface receptor.

Second messengers aid in the transmission of the signal within the cell by modifying the activity of target cellular proteins. Because they are small, second messengers can quickly spread throughout the cell through diffusion.

Water-soluble second messengers like cAMP diffuse through the cytosol (the fluid that fills the inside of a cell), while lipid-soluble second messengers like diacylglycerol (DAG) diffuse through the inner region of the plasma membrane where other signaling proteins are embedded.

Function of second messenger

As mentioned earlier, signal transduction can be carried out in two ways. The first is through receptor protein recruitment. Proteins have the capability to carry out specific interactions with other proteins, so these perform more complex functions in signal transduction. On the contrary, while they cannot perform complex functions, second messengers are much smaller and more mobile so they are able to quickly relay and amplify signals throughout the cell.

As such, when a quick, extensive response is required, second messengers are more prevalent in the signal transduction pathway.

Second messengers bind to specific protein targets, modifying them to relay signals downstream. These targets are usually enzymes whose catalytic activity is changed through the binding of second messengers. It is important to note that a second messenger does not only relay signals but also amplify them by activating multiple target proteins.

Second messenger examples

Let’s discuss a few prominent examples of second messengers. Here we will tackle calcium ions, IP3, DAG, and cAMP.

Calcium ions

Calcium ions (Ca²⁺) are often used as a second messenger by cells in pathways that are activated by both G protein-coupled receptors and receptor tyrosine kinases.

Cells tend to have very low concentrations of Ca²⁺ because ion pumps in the plasma membrane constantly remove it using adenosine-5'-triphosphate (ATP). When not in use, Ca²⁺ is stored in cytoplasmic vesicles in the endoplasmic reticulum or in intracellular storage compartments outside the cell.

During signal transduction, ligand-gated calcium ion channels allow larger quantities of Ca²⁺ present outside the cell to flow into the cytoplasm, increasing cytoplasmic Ca²⁺ concentration.

The increase in Ca²⁺ generates varied cellular responses, depending on the cell type that is involved. For instance, Ca²⁺ signaling causes insulin release in pancreatic β-cells, while an increase in Ca²⁺ in muscle cells causes muscular contractions. On the other hand, an increase in Ca²⁺ in plant cells can lead to greening in response to light.

Inositol triphosphate (IP3) and diacylglycerol (DAG)

The concentration of calcium in the cytosol can rise in response to a signal sent via a signal transduction pathway that allows Ca²⁺ to be released from the cell's endoplasmic reticulum.

Upstream, two more second messengers–inositol triphosphate (IP3) and diacylglycerol (DAG)--are involved in the pathways that lead to the release of Ca²⁺. These two messengers are created in the plasma membrane by the cleavage of a specific type of phospholipid.

IP3 travels from the plasma membrane to the cytoplasm where it binds to ligand-gated calcium channels found in the endoplasmic reticulum, causing the release of Ca²⁺ ions that carry on the signal cascade. On the other hand, diacylglycerol (DAG) stays behind in the plasma membrane where it activates protein kinase C (PKC). The activated PKC then phosphorylates serine and threonine residues in its target proteins.

Because IP3 activation is upstream of calcium in these pathways, calcium is actually the third messenger, but as mentioned earlier, scientists use second messenger as the blanket term for all small, nonprotein molecules involved in a signal transduction pathway.

Cyclic AMP (cAMP) second messenger system

Cyclic adenosine monophosphate (cAMP) is another example of a second messenger. cAMP is produced by adenylyl cyclase–an enzyme embedded in the plasma membrane–from adenosine triphosphate (ATP).

When cAMP binds to and activates an enzyme called cAMP-dependent kinase (A-kinase), the active A-kinase phosphorylates (and therefore activates) serine and threonine residues of target proteins. Many different types of cells contain A-kinase, and the target proteins in each cell type differ, giving rise to varying responses to cAMP in different cells.

Fig. 1 This diagram shows how cAMP functions as a second messenger in a signal transduction pathway.