Cellular Communication

Cells "Talk" To Each Other

Imagine you're eating some mint flavored ice cream. How does the dessert touching your tongue result in your brain knowing that this cold snack is disgusting and a flavor that should never be purchased? You'll probably answer with something like "because of your taste buds" but how do those work? The answer is cell communication. In essence, your cells are able to send messages or "talk" to each other.

What makes taste buds work? The answer is that those cells have certain proteins known as ligand receptors. These receptors, much like enzymes, have specific structures that allow only certain molecules to bind to them. Ligands are signaling molecules or chemical messengers. When this molecule binds to an appropriate receptor, it sends a message to a cell that causes a cascading effect resulting in some sort of response. This is known as cell communication, or cell signaling, and there are a variety of ways that it can happen.

Autocrine Signaling

Think about an automobile like a car. Being "mobile" means that something can move. The "auto" part of the word refers to "self" - an automobile can move itself. Autocrine signaling is when a cell sends a signal to itself.

Paracrine Signaling

What does it mean if we consider two people a pair? They're probably pretty close and often together. The root "para" means "next to" or "side by side".  In paracrine signaling, cells send a signal to a nearby cell that the ligands diffuse to.

Juxtacrine Signaling

Juxtacrine signaling, also known as "contact-dependent signaling," is a type of cell communication in which the cells are in physical contact with each other.

There are three types of juxtacrine signaling:

Endocrine Signaling

How does ADH, a hormone produced in the brain, affect water retention by kidneys? The answer is that it travels from the brain to the kidney through the blood. Hormones are a type of ligand produced by the endocrine system. Endocrine signaling involves hormones traveling far distances through the blood.

Why doesn't this affect the other cells it encounters during its travels? They don't have the proper receptors.

Signal Transduction

So what actually happens in cell communication? When the ligand reaches the cell, a process known as signal transduction occurs. During this process, the cell undergoes a series of changes before it eventually undergoes some sort of response as a result of the ligand.

The first step of signal transduction, and the part that sets everything off, is reception. In this step, the ligand binds to the ligand-binding domain of the ligand receptor. There are a variety of types of receptors, and they can be found on the membrane or within the cytoplasm.

After reception, the cell undergoes a domino-effect like process known as transduction. As a result of reception, the receptor protein changes (specifically in its intracellular domain). This then starts a series of downstream changes, which typically center on protein-protein interactions.

To learn more about different ways that reception or transduction can happen, take a look at some of these different types of receptors.

Intracellular Receptors

"Intra" means within; intracellular receptors are found within the cell - either in the cytoplasm or the nucleus. As such, the ligand must enter the cell to reach them, meaning that these ligands tend to be small and nonpolar, allowing them to passively travel through the membrane. In many cases, the response of these receptors involves modifying gene expression and turning certain genes on or off.

Ligand-Gated Ion Channels

How would you describe the function of a gate? Something to do with opening or closing, possibly? A ligand-gated ion channel is an ion channel that opens or closes based on the binding or a particular ligand. The ligand binds to the extracellular portion of the ion channel receptor, which causes it to modify cellular transport. These receptors are very common in the nervous system (particularly for neurotransmission at a synapse), but are also found in membrane-bound oranelles, such as the ER.

G-Protein-Coupled Receptors

GPCRs are the largest and most diverse category of receptors in eukaryotes. While they vary wildly in their ligands and responses, they all work in a fairly similar way. The GPCRs are a transmembrane protein (with 7 transmembrane alpha helices) that are bound to and work with a G protein - hence the name! An inactive G-protein has GDP bound to it, which is similar to ADP except it is made of a modified guanine rather than adenine. Upon binding of the ligand, the GPCR is modified and results in the activation of the G protein, in which GTP replaces the GDP.

Upon activation, the G protein leaves the receptor and diffuses along the internal membrane until it reaches, binds to, and activates an enzyme, which will trigger the next step of the transduction pathway. One of the main pathways that this can take includes the activation of adenylate cyclase, which produces cyclic AMP (cAMP) from ATP. cAMP is a second messenger, intracellular non-protein signaling molecules that amplify the signal. Amplification in this context means that the number of molecules activated in a step is a lot bigger than the number of molecules from the previous step.

The G protein also acts as a GTPase, and will hydrolyze the GTP, deactivating itself and returning to the GPCR so the process can begin again.

Receptor Tyrosine Kinases

RTKs are both receptor proteins and enzymes. Many of them exist as two inactive monomers that, upon the binding of ligands, dimerize as part of their activation. Once activated, the kinases adds a phosphate from an ATP molecule to the tyrosines on their tails. Once they are phosphorylated, they are "fully activated" and can now activate relay proteins and begin the transduction pathway.

RTKs are a special type of protein known as a kinase, which are enzymes that phosphorylate molecules, meaning they add a phosphate to them. Phosphorylation is a key aspect of cell signaling and is also often found in the transduction step (with phosphatases being enzymes that remove the phosphates). In a phosphorylation cascade, one kinase phosphorylates another, which phosphorylates something else in a chain reaction.

The descriptions under each type of receptor are not an all-inclusive discussion of how transduction happens. Second messengers (which are named because the ligand is the "first messenger") are used in the pathways of both GPCRs and RTKs. Phosphorylation occurs in transduction pathways often, with most cytoplasmic kinases phosphorylating other proteins rather than themselves like RTKs do.

The final step is known as response. This is when the cell does something which is the end goal of the signaling. This can range a lot and include movement, modification of gene expression, altered metabolism, and more. It is often caused by the final protein in that domino-effect-like process, the effector proteins.

Understanding Cell Signaling

There is a lot of variety in signal transduction pathways. If you look at (A), (B), and (C) in the image to the left, all cells have the same receptor and ligand, but have different pathways. Cells can respond to the same signal differently based on these pathways, and therefore signal transduction pathways have a very strong impact on how the cell responds to its external environment. As a particularly strong example of this, (D) shows that cardiac and skeletal muscles have exact opposite responses to the same ligand, acetylcholine.

Pathways are capable of working together or against each other, as seen in (C), which allows for greater variety and specificity in responses.

Proteins in the transduction step can activate or inhibit other proteins. If you look at (C) and focus on the star, the -> arrow pointing toward the green protein indicates the green protein is being activated. On the other hand, the -| arrow pointing toward the purple protein indicates it is being inhibited.

If the receptor protein's ligand binding domain is mutated, and the ligand cannot bind, it will prevent the response. That is not the only way the pathway can be impacted, however. Changes to any part of a signal transduction pathway can greatly change the cellular response.  If the yellow oval in (C) was mutated, it would be unable to activate the green and purple proteins, preventing their effects. If the star was overactivated, it would result in even less purple and even more green being activated. The changes impact the exact spot the change happens to as well as downstream components of the pathway.

In addition, similar to enzymes, chemicals and other molecules can interfere with the pathway as well. There are inhibitors that can block the initial receptor or that can inhibit molecules in the transduction pathway. Interfering with any component of the pathway can alter the pathway in some way, whether it be activation or inhibition.