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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.

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Second Messengers

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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.

Keep in mind that the signal transduction pathway involves multiple messengers and receptors. Second messengers are named as such because ligands which are external signaling molecules are considered the "first messengers."

However, the term "second messenger" may be confusing because there can be many different messengers in a signal transduction pathway. And what we might call “second messenger” may very well be the eighth messenger in the pathway!

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.

In a pathway, we typically refer to the interactions that take place prior to a certain point as upstream events and interactions that take place after that certain point as downstream events.

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.

Second messengers Figure 1: cAMP in signal transduction | StudySmarterFig. 1 This diagram shows how cAMP functions as a second messenger in a signal transduction pathway.

Phosphorylation means the addition of a phosphate group.

Have you ever heard of a disease called cholera? Cholera is a disease that typically occurs in places where the water supply is contaminated with human feces. When people consume contaminated water, they may acquire the cholera-causing bacterium called Vibrio cholerae which forms a film on the lining of the small intestine and produces a toxin. The cholera toxin is an enzyme that modifies a G protein that plays a vital role in controlling salt and water secretion. The G protein is fixed at an active state and rendered incapable of hydrolyzing guanosine triphosphate (GTP) to guanosine diphosphate (GDP). This means that the G protein constantly triggers adenylyl cyclase to produce cAMP.

As a result of the high cAMP concentration, the intestinal cells secrete significant amounts of salts into the intestines, followed by osmosis. The infected person develops diarrhea, which causes massive loss of water and salts from the body. Left untreated, cholera can be fatal.

Second Messengers - Key takeaways

  • 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.
  • Compared to proteins, second messengers are much smaller and more mobile so they are able to quickly relay and amplify signals throughout the cell.
    • Second messengers bind to specific protein targets, modifying them to relay signals downstream.
    • A second messenger does not only relay signals but also amplify them by activating multiple target proteins.

References

  1. 1. Zedalis, Julianne, et al. Advanced Placement Biology for AP Courses Textbook. Texas Education Agency.
  2. 2. Reece, Jane B., et al. Campbell Biology. Eleventh ed., Pearson Higher Education, 2016.
  3. Newton, Alexandra C., et al. “Second Messengers - PMC.” PubMed Central (PMC), www.ncbi.nlm.nih.gov, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968160/. Accessed 18 July 2022.
  4. OpenStaxCollege. “Hormones – Anatomy & Physiology.” Hormones – Anatomy & Physiology, pressbooks-dev.oer.hawaii.edu, http://pressbooks-dev.oer.hawaii.edu/anatomyandphysiology/chapter/hormones/. Accessed 18 July 2022.

Frequently Asked Questions about Second Messengers

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. 

Examples of molecules that act as a second messenger include calcium ions, inositol triphosphate (IP3), diacylglyerol (DAG) and cyclic adenosine monophosphate (cAMP).

Calcium ions are widely involved in signal transduction as a second messenger. 

Second messengers mainly relay and amplify signals transmitted by the binding of signaling molecules and cell-surface receptors.

An example of a hormone that uses a second messenger system is epinephrine.


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.

Test your knowledge with multiple choice flashcards

Second messengers are NOT __.

Second messengers bind to specific protein targets, modifying them to relay signals _____.

Which of the following are examples of second messengers?

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Do all ligands need second messengers? Why or why not?

No, not all ligands require second messengers. Some are able to pass through the cell membrane and interact with intracellular receptors in the cytoplasm or nucleus and directly alter transcription. 

Second messengers are NOT __.

Proteins

Compare how proteins and second messengers function in signal transduction.

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. 

Second messengers bind to specific protein targets, modifying them to relay signals _____.

downstream

How does a second messenger amplify a signal?

A second messenger amplifies a signal by activating multiple target proteins. 

Which of the following are examples of second messengers?

Calcium ions

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