Chemistry

Signal Transduction CAscades

Presented by: Tiffany Audlin, Latanya Barnes, Mercedes Garcia & Jennifer Olsen

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OBJECTIVES

Define Signal Transduction Cascades.

Explain how they work.

Explore factors that modulate their actions.

Examine how they are relative to psychopharmacology.

What is signal transduction cascade

A process where a chemical signal is transmitted through a cell

It allows for cellular communication

Stages

Reception

Transduction

Response

(Stahl, 2013)

Signal transduction cascade is a series of chemical reactions initiated by a stimulus acting on a receptor. Chemical signals are transmitted from outside the cell into the cell to elicit a response. Information is communicated to the cell. The process of signal transduction occurs in three main stages. The first stage is reception whereby the  receptor protein of the target cell detects the signal molecule from the exterior aspect of the target cell. The second stage is transduction whereby the binding of the signal molecule triggers the target cell’s receptor protein thus initiating transduction. The third stage involved in cell signaling is response. In this stage, the transduced signal eventually triggers a particular  cellular response. The response is usually in the form of cellular activity like activation of certain genes in the cell nucleus, cytoskeleton rearrangement, or catalysis usually by an enzyme such as Glycogen phosphorylase (Zhang, Tian, & Xing, 2016).

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How Signal Transduction Cascades Work

Signal transduction is the ability of the body cell to change its behavior or mode of action in response to receptor-ligand interactions.

In the cascade, ligand acts as the primary messenger.

The binding of a ligand to the receptor results in the production of second messengers or molecules within the target cell (Zhang, Tian, & Xing, 2016).

The second messengers are responsible for relaying the signal to a different location, for instance, from the plasma membrane to the nucleus.

This mechanism results in the occurrence of a cascade of change within the target cell causing a change in the identity or function of the cell.

How Signal Transduction Cascades Work

Signal transduction or cell signaling involves transmission of the molecular signals from the exterior aspect of the cell to the interior aspect.

The signaling information is often transmitted from the receptors in the plasma membrane through the cytoplasm, nucleus, cytoskeleton, and other subcellular compartments.

The signal transduction cascade plays a key role in the amplification of the cellular response to  an external signal (Russell, & Cotter, 2015).

The messenger molecules involved in cell signaling may be peptides, amino acids, fatty acids, proteins, lipids, nucleotides, or nucleosides.

 The signal-transduction cascades are involved in the mediation of the processes of sensing and processing a stimuli. The molecular circuits are responsible for detection, amplification, and integration of diverse external signals for generation of responses like changes in ion-channel activity,  gene expression, and enzyme activity.   The signaling information is transmitted to the cell nucleus if the response is gene transcription. One of the classical second messengers involved in the amplification of the signal is calcium ions. Water-soluble second messengers like cGMP and cAMP act by diffusing into the cytosol just like calcium ions while the lipid-soluble second messengers like diacylglycerol (DAG)  act by diffusing along the plasma membrane. The common means in which information is transferred in cell signaling is protein phosphorylation (Russell, & Cotter, 2015).

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Factors that Can Modulate the Signal Transduction Pathways

Understanding Allosteric Modulators

An allosteric modulator is a substance that indirectly influences the effects of a primary ligand that directly activates or deactivates the function of a target protein. They are modulators that bind to a site different from the neurotransmitter(Wikipedia, 2019). This “other site” is referred to as allosteric. Allosteric Modulators can either boost or block the action of the neurotransmitter(Stahl, 2013).

Positive allosteric modulators (PAMs): Boosts what the neurotransmitter does. Referred to as enhancers or potentiators that ignite an amplification of the effect of receptor’s response to the primary ligand without directly activating the receptor.

Example:  Benzodiazepines act as PAMs by boosting the action of GABA(Stahl, 2013) .

Negative allosteric modulators (NAMs): Blocks what the neurotransmitter does. Act at a different site(allosteric) to reduce the responsiveness of the receptor to the endogenous ligand(Stahl, 2013).

Note: Allosteric modulators have little or no activity on their own in the absence of a neurotransmitter. When a neurotransmitter it not binding to its site, the allosteric modulators do not work(Stahl, 2013).

One of the factors that can modulate or indirectly influence the transduction pathways are  allosteric modulators. The term allosteric means that they affect the action from a site different from the neurotransmitter. Allosteric modulators can either boost or block the neurotransmitters action. Modulators can be categorized as either positive or negative. A positive allosteric modulator will indirectly enhance the effect and the negative allosteric modulator will reduce the responsiveness or effect.

It is important to point out that allosteric modulators have little or no activity on their own in the absence of a neurotransmitter. When a neurotransmitter it not binding to its site, the allosteric modulators do not work.

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FACTORS THAT CAN MODULATE THE SIGNAL TRANSDUCTION PATHWAYS

Allosteric Modulation: PAMS and NAMS (Simons, 2019).

FACTORS THAT CAN MODULATE THE SIGNAL TRANSDUCTION PATHWAYS

Some things to consider about the Agonist Spectrum:

Neurotransmitters that occur naturally are considered agonist (Stahl, 2013).

Some drugs are considered agonists because they stimulate receptors(Stahl, 2013).

Some drugs stimulate receptors to a lesser degree than natural neurotransmitters therefore they are considered partial agonists(Stahl, 2013).

Although antagonists block the action of agonist it is important to understand that they are not opposite from one another because antagonists have no activity of their own without an agonist. Therefore, another name for antagonist is “silent”. (Stahl, 2013).

The Inverse agonists do have the opposite action of the agonist because they can block and reduce activity even if there is  no agonist presence(Stahl, 2013).

Stahl, 2013.

This image shows the agonist spectrum. Both naturally occurring neurotransmitters and drugs can be agonists. When drugs stimulate receptors to a lesser degree than a natural neurotransmitter they are called partial agonists. Antagonists can have a blocking action but only if an agonist is present.  As you can see from the image, the inverse agonist is the opposite of an agonist because it can block and reduce activity even without the agonist present.

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Signal Transduction Cascades and how it’s relative to psychopharmacology

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Neurotransmitters, hormones and drugs transfer their signals to cells by interacting with a membrane receptor at the cell surface (Stahl’s, 2013, Ch.1).

The cell then responds with a series of intracellular events that lead to altered cellular functions (Stahl’s, 2013, Ch.1).

This alteration in cellular function may in turn affect the function of a tissue, organ or body system (Stahl’s, 2013, Ch.1).

Let’s look at SSRI’s

SSRI’s such as Citalopram, Fluoxetine, Paroxetine and Sertraline ease depression by increasing levels of serotonin in the brain.

Serotonin is a chemical messenger that carries signals between nerve cells in the brain.

After carrying a message, serotonin is reabsorbed by the nerve cells.

SSRI’s inhibit the reabsorption of serotonin in the brain, making more serotonin available to pass further messages between nearby nerve cells

(Sangkuhl, Klein & Altman, 2009)

Let’s look at central nervous system agents

Levodopa works to treat Parkinson symptoms because it replaces the chemical messenger dopamine, which the brain can no longer make.

Levodopa is a precursor to dopamine that travels directly to the brain.

Outside the brain our bodies contain proteins that break down levodopa. The first protein called DOPA (decarboxylase) is the protein that turns levodopa into dopamine.

When levodopa is turned into dopamine outside the brain it causes people to feel nauseated.

Today, levodopa is combined with carbidopa which blocks DOPA (decarboxylase) outside the brain allowing more of the levodopa to get into the brain therefore decreasing the s/e from having dopamine outside the brain.

(Port, 2017)

When providers understand the specific molecular receptors and signal transduction cascades necessary to modulate the different neurotransmitters that relate to neurological illnesses, they will be able to predict possible drug interactions, improve upon therapeutic strategies and enhance the quality of their patient’s life.

References

Port, B. (2017, October 9). How do levodopa medications work? Retrieved from https://medium.com/parkinsons-uk/how-do-levodopa-medications-work-ac6a6e58e143

Russell, E. G., & Cotter, T. G. (2015). New insight into the role of Reactive Oxygen Species (ROS)

in cellular signal-transduction processes. In International review of cell and molecular biology (Vol. 319, pp. 221-254). Academic Press.

Sangkuhl, K., Klein, T., & Altman, R. (2009). Selective serotonin reuptake inhibitors (SSRI) pathway. Pharmacogenet Genomics, 19(11), 907-909. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896866/

Simons, L. (2019). The Science of Parkinson’s. Retrieved from https://scienceofparkinsons.com/tag/positive-allosteric-modulator/

Stahl, S. (2013). Essentials of Psychopharmacology, (4th edition). United Kingdom, Cambridge  University Press, ISBN-13: 978-1107025981

Wikipedia., (2019)., Allosteric Modulators., Retrieved from https://en.wikipedia.org/wiki/Allosteric_modulator#targetText=In%20biochemistry%0and%20pharmacology%2C%20an,f unction%20of%20a%20target%20protein.

Zhang, J., Tian, X. J., & Xing, J. (2016). Signal transduction pathways of EMT induced by TGF-β, SHH, and WNT and their cross talks. Journal of clinical medicine, 5(4), 41.

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