Cell Signaling (Signal Transduction Pathways)

Have you ever wondered about how different kinds of molecules create different cellular responses? If that sentence doesn't mean anything to you, let me rephrase it. Have you ever wondered about how one type of signaling molecule, for example, adrenaline, causes your heart cells to beat faster but your causes your liver to produce and release sugar? How does one molecule produce different responses in different types of cells? 

Well, to understand this, we must understand the how the different proteins in the cell membrane start signaling responses at all, and to understand that, we must understand the cell membrane and the type of organelle it is. 

So far, we know the cell membrane is made of phospholipids and has proteins embedded in it - but that's about all we know. The cell membrane is actually fluid - the phospholipids frequently switch places and pop around, incredibly fast, of course, and fluidity in the membrane is often different in different areas. One important note is that phospholipids are influenced by temperature - the cell membrane could come apart if the temperature isn't right, and that would mean death for the cell. To prevent this, cholesterol is also placed into the membrane to decrease these effects. 

The cell membrane, as I mentioned a second ago, is also chock full of proteins. These proteins include:

• Integral proteins: located inside the membrane

• Peripheral proteins: attached to the membrane

These proteins perform many functions. They help in transport, enzymatic activity, signal transduction (what we will be discussing), cell-cell recognition, intracellular joining, and cytoskeleton and extracellular matrix attachment. The membrane is made of glycolipids and glycoproteins, where are combinations of lipids and carbohydrates and proteins and carbohydrates. 

An example of a membrane protein is an aquaporin. Aquaporins regulate the water content inside the cell by allowing 3 billion water molecules in or out of the cell per second in a single file line, with 10 water molecules inside the protein at once. 

When a cell wants to expel a compound, they use exocytosis, a process by which vesicles carrying material merge with the plasma membrane and push the compound out. Endocytosis is the opposite of this, it is the process by which the cell creates vesicles from the cell membrane to intake new molecules. But both exo- and endocytosis are types of active transport and are done with the help of proteins.

Another important note is about different types of chemical pathways that are followed within cells. Here are a few:

1. Metabolic pathway: this pathway starts with one molecule and alters it.

2. Catabolic pathway: this pathway starts with a complex molecule and breaks it.

3. Anabolic pathway: this pathway consumes energy to build a complex molecule.

Entropy, the measure of disorder or randomness, happens in spontaneous processes, or processes that do not require an energy input and increase entropy.

Free energy is energy that can perform work when the temperature and pressure are constant. Enthalpy is the total energy of a biological system. Within biological systems, there are two types of reactions that involve energy. These are exergonic and endergonic reactions. Exergonic reactions are spontaneous and result in a net release of energy. Endergonic reactions are non-spontaneous and result in a net input of energy. 

Alright, we are clearly more comfortable with the cell membrane now and its transport proteins, so let's discuss the actual process of how a cell responds to a stimulus. First, a receptor protein on the cell's surface binds to a ligand, a molecule that binds specifically to a receptor site on another molecule.

Then, the receptor protein undergoes a change in shape. This change in shape causes another protein to bind to the receptor protein, setting off a signal transduction pathway. This process itself occurs in three steps:

• Reception: The signaling molecule binds to a target cell.

• Transduction: The binded protein changes shape, activating other changhes in relay molecules, creating a signal transduction pathway that eventually activates a response.

• Response: The cell responds to the signal. 

So, what proteins do the ligands bind to, what is the pathway, and how does the pathway work to cause different cellular responses?

These are all some great questions, which I am going over now. Let's answer the first one. What proteins do the ligands bind to?

1. GPCRs, or G protein-coupled receptors. GCPRs are cell surface receptors that work with a G protein, which binds GTP (an energy-rich molecule just like ATP, except that it utilizes guanine instead of adenine). They perform many functions and are used commonly, even to help us with our senses of vision, smell, and taste. 

2. RTKs, or receptor tyrosine kinases. RTKs belong to a major class of receptors characterized by having enzymatic activity. A kinase catalyses phosphate group transfer. These receptors attach phosphates to tyrosine (an amino acid). RTKs can access many transduction pathways while GPCRs can only activate one. Proteins can be activated through phosphorylation - in fact, these protein kinases can cause a phosphorylation cascade until they cause a response. Protein phosphatases rapidly remove phosphate groups from proteins, allowing these reactions to occur quickly. 

3. Ligand-gates ion channels. These molecules contain gate-like regions that close or open if a signaling ligand binds to it. This allows or blocks the flow of specific ions like Na+ or Ca2+.

After binding to these molecules and changing their shape, the new shape of the protein cause other molecules to bind to the receptor that then phosphorylize (transfer a phosphate group to) other proteins, which activates them and causes them to phosphorylize other proteins. This creates a phosphorylation cascade that then initiates the proteins necessary to carry out the appropriate response in the cell. The proteins involved in the cascade are then known as relay proteins. Unbelievable, right? I'll add some pictures to help understand this below.

We have yet to answer the last question, so let me explain it now. If you don't remember, the question was, "how does the pathway work to cause different cellular responses?" I mentioned that the signal transduction pathway activates relay proteins and eventually the proteins needed to cause a reaction. The difference is simply: different types of cells have different proteins! Each type of cell has its own set of proteins, which causes different relay responses and overall different cellular responses in the cell to signaling molecule. I put pictures of different types of relays from a single ligand below as well, to show you how the different relays lead to different responses.

This process is incredible, and so useful and amazing. It is used in so many different places. Bacteria use this process to do something called quorum sensing, which allows them to determine the density of cells around them by monitering the concentration of signaling molecules in their environment. This process is used to commence apoptosis, or cell suicide. It is also used to tell cells to grow or divide in a certain area through the use of growth factors. Cells use it for different kinds of signaling as well: Paracrine signaling involves a secreting cell sending signals to a target cell. Synaptic signaling is what nerve cells use to send chemical signals to other nerve cells or muscle cells. And long-distance signaling is done by endocrine cells to secret hormones into body fluids. Since different cells have different proteins sets (and thus different receptors on their surface), hormones end up reaching all the cells but only bind to some.

Overall, signal transduction pathways are very complicated, and they get even more complicated. I skimmed the surface with this page, so I highly advise reading this article, which goes further in depth and uses examples of signaling pathways - I only have so much time to write, so I cannot include everything.

But, I will help you guys with one example of a signaling pathway: let's go with adrenaline, or epinephrine.

First, we can clearly see that the epinephrine binds with the receptor, which in this case is a GCPR. This causes a G protein to bind to the receptor and activate adenylyl cyclase, which turns ATP into another molecule called cAMP. cAMP then activates a protein kinase, which activates a phosphorylase kinase, which (not shown in the picture above) activates glycogen phosphrylase. This converts glycogen to glucose which can be burned in cellular respiration to provide quick energy. 

While this was a very quick and simplified description of what happens during an adrenaline rush in your cells, it is sufficient to help you connect the concepts I talked about earlier.

Cell signaling is an insanely complicated topic that confuses many scientists today, and how it works is just unbelievable. There are so many factors involved, and it gets very complicated very quickly. If you want to know more, contact me at twisha.sharma30@gmail.com. That's all I have for you in this page, though. Thank you for reading and I'll see you in the next one!