1The idea in one paragraph

Cells talk in molecules. A cell releases a signalling chemical, the ligand, and another cell responds only if it has a receptor: a protein with a binding site that fits that ligand and no other. Binding changes the shape of the receptor, and that change sets off a chain of events inside the cell, a signal transduction pathway, that ends in a response: a channel opens, an enzyme switches on, a gene is transcribed. Where the receptor sits depends on the ligand. A ligand that cannot cross the membrane binds a receptor in the membrane and never enters; a ligand that dissolves in lipid slips through and meets its receptor inside. Three transmembrane mechanisms and one intracellular one are named by the guide, and each has an example you must know.

2Ligands and receptors

A ligand is any molecule that binds specifically to a site on another molecule. In signalling, the ligand is the signalling chemical, and the guide asks you to call it by that name. A receptor is a protein with a binding site for one particular ligand.

The fit is like an enzyme and its substrate from C1.1. The binding site has a shape, and it has chemistry: R groups that are charged, polar or hydrophobic in exactly the right places. Only a ligand that matches both can bind. Figure 1 draws the two outcomes.

Two things follow, and they are the answer to the question this unit asks.

A cell hears only the signals it has receptors for. Blood carries dozens of hormones past every cell in the body, all the time. A cell responds to a hormone only if it makes the receptor for it; every other hormone passes by unnoticed. A target cell is simply a cell with the right receptor.

The receptor, not the ligand, carries the message inside. Binding changes the receptor's conformation, and that change is what triggers the response. The ligand is released again unchanged. It is a key that turns a lock; it does not walk through the door.

The binding is reversible. When the concentration of ligand falls, ligands leave their receptors and the signal stops. That is how a cell senses how much signal there is, not just whether there is any.

3Quorum sensing in bacteria

Signalling is older than animals. Quorum sensing is signalling between bacteria that lets a population act together once it is dense enough. Each cell releases a small signalling molecule, called an autoinducer, into its surroundings, and each cell also has receptors for it. When there are few cells, the autoinducer diffuses away and its concentration stays low. When there are many cells in a confined space, the autoinducer builds up. Past a threshold concentration enough receptors are occupied to switch on particular genes in every cell at once.

The guide's example is bioluminescence in the marine bacterium Vibrio fischeri. Free in seawater, at low density, it does not glow. It also lives inside the light organ of the Hawaiian bobtail squid, packed at very high density, and there it glows. Figure 2 shows the two situations and the switch between them.

The sequence to learn:

1. Each V. fischeri cell makes the autoinducer at a low rate, and it diffuses out of the cell.
2. At high cell density the autoinducer concentration rises, because many cells release it into a small volume.
3. The autoinducer diffuses back into the cells and binds a receptor protein inside them.
4. The activated receptor switches on transcription of the genes for luciferase, the enzyme that makes light, and the light organ glows.
5. The same genes include the one for making more autoinducer, so once the threshold is passed production accelerates. That is positive feedback (section 13), and it makes the switch sudden and shared.

Why only at high density? Making light costs a lot of ATP. One bacterium glowing alone in the ocean wastes energy for nothing; a dense colony glowing together makes a light bright enough to be useful. The squid benefits too: at night the glow from its underside matches the moonlight coming from above, so a predator looking up does not see the squid's shadow. The bacteria get a sheltered, food-rich home. Quorum sensing is how the bacteria "know" they are in the squid rather than in open water.

4Four kinds of signalling chemical in animals

The guide names four functional categories. Learn what makes each one different, because "distinguish" questions ask exactly that.

Calcium ions are the odd one out, and that is why they are on the list. A cell keeps the concentration of Ca²⁺ in its cytoplasm very low, by pumping it out or into internal stores. When channels open, Ca²⁺ floods in, binds to proteins, and changes their shape. The signal is switched on and off by moving the ion, not by making or destroying it. Ca²⁺ therefore works as a signal within a cell, usually as a step in a longer pathway that started with a different ligand outside.

5Why so many different chemicals?

Hormones fall into three chemical groups, and the guide wants all three:

• Amines, small molecules made from a single amino acid: epinephrine, melatonin.
• Proteins and peptides, chains of amino acids: insulin, glucagon, antidiuretic hormone, FSH, LH.
• Steroids, made from cholesterol: oestradiol, progesterone, testosterone, cortisol.

Neurotransmitters come from an even wider range: amino acids (glutamate, glycine, GABA), peptides (endorphins), amines (dopamine, serotonin, norepinephrine), acetylcholine in a group of its own, and even a gas, nitric oxide (NO). The guide prints "nitrous oxide" here; the gas that acts as a neurotransmitter is nitric oxide, NO, and that is the name to write.

Why use so many? Four reasons, and a "suggest" question takes any two.

• Every message needs its own ligand. If one chemical carried two messages, a cell could not tell them apart. Hundreds of distinct signals need hundreds of distinct shapes.
• Solubility decides how the signal works. A hydrophilic protein cannot cross a membrane, so it must act through a surface receptor, which gives a fast response. A hydrophobic steroid crosses the membrane, reaches the nucleus and changes gene expression, which gives a slow, long-lasting one. A body that needs both kinds of response needs both kinds of chemical.
• Speed of making and removing. A small neurotransmitter can be made quickly and broken down within milliseconds, which is what a synapse needs; a protein hormone can circulate for minutes.
• A gas reaches everywhere nearby. Nitric oxide diffuses straight through membranes in every direction and breaks down within seconds, so it acts only around its source.

6Near and far

A signal's reach depends on how the ligand gets there. Figure 3 puts the two extremes side by side.

A neurotransmitter is released into a synaptic gap about 20 nanometres wide and diffuses across in a fraction of a millisecond. It affects the one cell on the other side and is removed almost at once. The effect is localized, fast and brief.

A hormone is secreted into the blood and carried to every part of the body within about a minute. Any cell with the right receptor responds, so one hormone can change many organs at once: epinephrine reaches heart, liver, lungs and skeletal muscle together. The effect is distant, slower to begin and longer lasting.

The comparison is what earns marks: "a hormone is transported by the blood to distant target cells, whereas a neurotransmitter diffuses across a synaptic gap to an adjacent cell."

7Two places for a receptor

Where the receptor sits depends on one property of its ligand: can it cross the phospholipid bilayer? Figure 4 draws both answers.

A transmembrane receptor binds a hydrophilic ligand that cannot pass the hydrophobic core, so the ligand stays outside and the message crosses as a change in the receptor's shape. The section inside the bilayer has hydrophobic amino acids facing the fatty acid tails; the parts either side have hydrophilic ones facing water. An intracellular receptor binds a hydrophobic ligand, above all a steroid, that diffuses into the cell; surrounded by water, the receptor has a mainly hydrophilic surface.

8Signal transduction

Signal transduction is the conversion of a signal outside a cell into a response inside it. Binding of the ligand is only the start. The receptor changes shape; that change activates the next molecule; that one activates the next. Each step is a change of shape or a chemical modification of a protein, and the chain ends in the response.

Several steps give two advantages over a single switch: amplification, because each activated enzyme activates many molecules of the next, and control, because every step is a point where other signals can speed the pathway up or shut it down. The next four sections are the four starts the guide names.

9Receptors that are ion channels: acetylcholine

The simplest pathway has one step. The acetylcholine receptor, found for example at the junction between a motor neuron and a muscle fibre, is itself an ion channel through the membrane. Figure 5 shows it shut and open.

1. Acetylcholine binds to binding sites on the outer face of the receptor.
2. The receptor changes shape and a channel through its centre opens.
3. Positively charged ions, mainly Na⁺, diffuse into the cell through the channel.
4. The inside of the membrane becomes less negative. The membrane potential, the voltage across the membrane, has changed.

That change of voltage may cause other changes: in a neuron it may start a nerve impulse, and in a muscle fibre it starts contraction. C2.2 takes this story on. The receptor is closed again within milliseconds, because an enzyme in the gap breaks acetylcholine down.

10G protein-coupled receptors and epinephrine

G protein-coupled receptors (GPCRs) are transmembrane receptors that pass their signal to a G protein on the inside face of the membrane. The G protein is a switch: it is off when it carries GDP and on when it carries GTP. Humans have hundreds of different GPCRs, including the receptors for most smells, and a large share of medicines work by binding to one of them.

The guide's example is epinephrine (adrenaline), the hormone that prepares the body for vigorous activity. Figure 6 follows it into a liver cell.

1. Epinephrine, carried in the blood, binds to its receptor on the outside of the plasma membrane. It does not enter the cell.
2. The receptor changes shape and activates a G protein inside the membrane: the G protein releases GDP and binds GTP.
3. Part of the activated G protein moves to an enzyme in the membrane, adenylyl cyclase, and activates it.
4. Adenylyl cyclase converts ATP into cyclic AMP (cAMP). cAMP is the second messenger: a small molecule that carries the signal through the cytoplasm. Epinephrine was the first messenger.
5. cAMP activates a protein kinase, an enzyme that adds phosphate groups to other proteins.
6. The kinase switches on the enzymes that break down glycogen, and the liver cell releases glucose into the blood, fuel for the muscles.

Each step multiplies the signal. One adenylyl cyclase makes many cAMP molecules; each active kinase phosphorylates many enzymes; each of those releases many glucose units. One molecule of hormone outside ends in a very large number of glucose molecules. The pathway also switches off quickly: the G protein converts its GTP back to GDP, and cAMP is broken down, so the response stops soon after epinephrine is gone.

On the two names. The hormone is made by the adrenal glands, which sit on top of the kidneys. "Adrenaline" was built from Latin (ad, at, and ren, kidney) and "epinephrine" from Greek (epi, above, and nephros, kidney). Both were coined by researchers, and unusually both are still in everyday use in different parts of the world. Agreed naming is a form of international cooperation in science: a name everyone recognises lets a result in one country be checked and used in another. Write either name in the exam.

11Receptors with tyrosine kinase activity: insulin

The insulin receptor is a transmembrane receptor that is also an enzyme. Its inside part is a tyrosine kinase: it adds phosphate groups to the amino acid tyrosine. Figure 7 follows the pathway.

1. Insulin, a protein hormone, binds to the receptor on the outer surface of a target cell, such as a muscle or fat cell.
2. The receptor changes shape, and its tyrosine kinase part phosphorylates tyrosines on the receptor's own inner surface.
3. The phosphorylated tyrosines are recognised by relay proteins inside the cell, which bind and are activated.
4. A sequence of further reactions follows.
5. It ends with the movement of vesicles containing glucose transporters to the plasma membrane. The vesicles fuse with the membrane, and the transporters become part of it.
6. With more transporters in its membrane, the cell takes up glucose faster by facilitated diffusion, and blood glucose falls.

Notice what insulin does not do. It does not enter the cell, and it does not carry glucose. It changes how many doors the membrane has.

12Intracellular receptors: steroids and genes

The steroid hormones oestradiol, progesterone and testosterone are hydrophobic. They diffuse through the plasma membrane and bind to receptors inside the cell. Figure 8 shows what happens next.

1. The steroid diffuses through the plasma membrane into the cytoplasm.
2. It binds a site on its receptor, in the cytoplasm or the nucleus, and activates it.
3. The hormone–receptor complex binds to specific DNA sequences next to particular genes.
4. This promotes transcription of those genes. New mRNA is made, then new proteins, and the proteins change what the cell does.

Because the pathway runs through gene expression, it is slower than the transmembrane ones (hours rather than seconds) and its effects last longer.

The guide asks for two target cells.

Oestradiol and the hypothalamus. Some cells in the hypothalamus secrete gonadotropin-releasing hormone (GnRH), which makes the pituitary gland release FSH and LH. Oestradiol from the growing follicles in the ovary acts on these GnRH-secreting cells. When oestradiol is high and rising in the days before ovulation, the effect is to increase GnRH secretion; the pituitary releases more LH and FSH, and the result is the surge of LH that triggers ovulation. At lower levels, earlier in the cycle, oestradiol has the opposite, damping effect on the hypothalamus and pituitary. The whole cycle is in D3.1; here you need the target cell and the response.

Progesterone and the endometrium. After ovulation the corpus luteum secretes progesterone, which binds to receptors in the cells of the endometrium, the lining of the uterus. The genes it promotes maintain the thickened lining and prepare it to receive an embryo: more blood vessels, and glands that secrete nutrients. If progesterone falls, as it does when no pregnancy begins, the lining is no longer maintained and it breaks down in menstruation.

13Positive and negative feedback

A signalling pathway is regulated by its own output. There are two forms, and Figure 9 draws one example of each.

Negative feedback: the response reduces the stimulus that caused it. It returns a variable to a set level and keeps it stable. Example: after a meal, blood glucose rises; β cells in the pancreas secrete insulin; body cells take up glucose; blood glucose falls, and as it falls less insulin is secreted. The response has removed its own cause.

Positive feedback: the response increases the stimulus that caused it. The change speeds up and runs to an end point instead of settling. Example: rising oestradiol makes the hypothalamus secrete more GnRH, the pituitary releases more LH and FSH, the follicle grows and secretes even more oestradiol, and the loop drives the LH surge until ovulation ends it. Quorum sensing in section 3 is another case: autoinducer switches on the gene for making more autoinducer.

Negative feedback reverses a change and keeps a level stable. Positive feedback amplifies a change until something outside the loop stops it.

Negative feedback is found at every level of biological organisation, because most things must be kept steady. Positive feedback is rarer and always has a natural end point: an ovulation, a birth, a blood clot.