Cell communication

Paracarine signalling is a type of chemical signalling where molecules diffuse over relatively short distances to neighbouring cells.

An example is the secretion of growth factors – compounds that stimulate cell division. A single cell can secrete a growth factor, which can then be received by multiple nearby cells.

Synaptic signalling is a type of paracrine signalling that is unique to neuronal cells. This type of signalling combines electrical and chemical signals: electrical impulses travel down the length of a neuron and trigger release of neurotransmitters, which then induces a second electrical impulse in another neuron.

Endocrine signalling occurs over long distances.

Specialised endocrine glands synthesise and secrete hormones into body fluids, most commonly blood.

Hormones are then carried throughout the body and reach virtually every cell. Only cells which have specific receptors for the hormone can respond to the signal.

Autocrine signalling is when the cell signals to itself.

The signal molecule binds to a receptor on that same cell. This is to help the cell adopt and reinforce its identity during development and differentiation.

Aberrant autocrine signalling can lead to uncontrolled cell division and dedifferentiation, which eventually results in cancer.

Contact-dependent signalling occurs between cells that are physically touching each other.

Intracellular mediators are chemical molecules that pass from one cell to another via small protein channels in the touching membrane. This type of signalling is helpful to coordinate cellular responses in tissues.

For example, epithelial cells stop dividing once they reach a continuous layer of single cells.

Reception is the process by which a signal molecule binds to a protein on the target cell, to elicit a cellular response.

Each receptor has a set of ligands – molecules that can trigger the receptor. Receptors can be found either on the outside or inside of the cell surface.

G protein-coupled receptors (GPCRs) account for 60% of all known cellular receptors in humans. They contain a transmembrane protein that supplies a ligand binding surface on the extracellular side and surface for G proteins on the intracellular side

A G protein, which is much smaller and capable of binding to guanosine triphosphate (GTP). GTP is an energy-rich molecule, very similar to ATP.

While inactive, the two portions of a GPCR float separately in the membrane. An inactive G protein is bound to guanosine diphosphate (GDP) – the hydrolysed product of GTP.

When a ligand binds to the transmembrane protein, it changes shape and binds the G protein to bind.

Binding then alters the shape of the G protein, which allows GDP to be displaced by GTP.

This activates the G protein. It then dissociates from the transmembrane receptor, finds a relay molecule in the membrane – usually an enzyme – and activates it.

The relay protein is the next step in the signalling cascade and takes over the transduction of the signal.

Meanwhile, the G protein hydrolyses its GTP to GDP and returns to an inactive form.

Receptor tyrosine kinases are unique receptors because they also act as enzymes.

While inactive, the two halves of a receptor tyrosine kinase float freely in the membrane.

When a ligand binds, the two halves associate and form a functional enzyme.

This enzyme then hydrolyses ATP and adds 6 phosphate groups onto itself.

Once phosphorylated, the receptor tyrosine kinase can activate relay molecules.

Eventually, receptor tyrosine kinases are dephosphorylated and return to an inactive state.

Ligand-gated ion channels only open when they detect an extracellular ligand.

While it is bound, the ion channel is open, and ions can flow freely along their concentration gradient.

When the ligand dissociates, the channel closes.

These types of receptors are the basis of synaptic signalling in the nervous system: binding of neurotransmitters to such channels and the resulting flux of ions generates an electric impulse.

Intracellular receptors only detect ligands that can easily cross the plasma membrane: these are generally steroid hormones and small gases.

These receptors can reside either in the cytoplasm or in the nucleus. In many cases, when a ligand binds to an intracellular receptor, it will act as a transcription factor in the nucleus. This means that the ligand-receptor complex can turn the expression of certain genes on and off.

For example, many sex hormones are steroids. When testosterone binds to its receptor in the male testes, it can trigger the expression of genes involved in spermatogenesis.

Transduction involves the activation of a protein.

Often, activation of a protein refers to phosphorylation or dephosphorylation – addition or removal of phosphate groups.

Phosphate groups are very small compared to the size of a whole protein, but they can drastically change the protein’s three-dimensional shape (conformation) and influence which other proteins can or cannot interact with it.

An enzyme that adds phosphate groups is called a kinase (like receptor tyrosine kinase), while an enzyme that removes phosphate groups is called a phosphatase.

Some signal transduction pathways are a series of kinases, all of which are free-floating in the cell in their inactive form.

When phosphorylated, these kinases become active and phosphorylate the next kinase in the sequence, forming a phosphorylation cascade.

Eventually, the last kinase phosphorylates a functional protein that produces a cellular response. Phosphatases are continuously active and dephosphorylate the kinases to shut off the transduction pathway before it gets out of hand. Thus, whether a cell produces a response or not depends on the balance between kinases and phosphatases.

Signal transduction can sometimes require small molecules, collectively called second messengers. These are cAMP, inositol triphosphate and ions. In these pathways, the receptor triggers an enzyme that produces these small molecules, while the final steps of the pathway include proteins that are sensitive to them.

For example, cAMP is produced by adenylyl cyclase, while cAMP itself triggers protein kinase A. Meanwhile, is produced by phospholipase C; triggers the release of intracellular stores, which leads to activation of response proteins.

The final step of a signalling pathway is a cellular response.

Intracellular receptors can directly regulate the expression of certain genes, although other receptor types can also achieve this type of response.

Other possible responses include, but are not limited to:

• Boosting or dampening the activity of a particular protein
• Opening or closing an ion channel
• Switch to a different metabolic pathway
• Release of stored compounds, e.g., glucose
• Cell division, growth or death

Cellular signalling pathways are long and complex. However, there is a rationale as to why this is an effective form of cell communication.

1. Reliance on multiple molecules throughout the signalling cascade amplifies the response. Each relay molecule in a phosphorylation cascade can activate multiple other molecules, which in turn activates even more molecules and so on. Eventually, the cell ends up with not just one, but hundreds of active copies of response proteins. This is necessary for fast and definite responses.
2. Since there are so many steps in the signal transduction pathway, they can be regulated at any one point. This ensures that the signal is specific to a particular response protein and coordinated with other signalling pathways (which may be acting in the opposite direction! It is a balancing act).
3. Despite there being so many components involved, most signalling pathways are very efficient due to scaffolding proteins which keep all the necessary kinases, enzymes and second-messenger-sensitive proteins held in one place.
4. At any point, the signal can be terminated. Having multiple termination points again ensures a fast and complete switch-off.