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C2.1

Chemical signalling

Theme C · Interaction and interdependence · Cells · Additional higher level only

This entire topic is additional higher level. SL candidates are not examined on any of it. Cells are surrounded by chemical messages, and each cell responds only to the ones it has receptors for. This topic is about how that works: what kinds of signalling chemicals there are, where their receptors sit, and how binding on the outside of a cell becomes a change on the inside. A small number of mechanisms — ion channels, G proteins, tyrosine kinases, intracellular receptors — account for almost all of it.

🎯What you need to be able to do

  • Describe receptors as proteins with binding sites for specific ligands.
  • Explain quorum sensing, using bioluminescence in Vibrio fischeri.
  • Distinguish hormones, neurotransmitters, cytokines and calcium ions as categories of signalling chemical.
  • Outline the chemical diversity of hormones and neurotransmitters, and contrast localized and distant signalling.
  • Distinguish transmembrane receptors from intracellular receptors.
  • Explain how receptors initiate signal transduction pathways.
  • Explain the acetylcholine receptor, G protein-coupled receptors, the adrenaline receptor with cAMP, and the insulin receptor’s tyrosine kinase activity.
  • Explain how steroid hormones act on intracellular receptors, and the effects of oestradiol and progesterone on their target cells.
  • Distinguish positive and negative feedback in the regulation of signalling pathways.

📚The biology

Receptors and ligands

A receptor is a protein with a binding site for a specific signalling chemical. The signalling chemical is called the ligand. Binding depends on complementary shape and chemical properties, like an enzyme and its substrate, but the ligand is not changed by binding. Only cells that have the right receptor respond to a given ligand, which is how a hormone circulating in the blood past every cell affects only its target cells.

Quorum sensing in bacteria

Even bacteria signal to each other. In quorum sensing, each bacterium releases a small signalling molecule (an autoinducer) into its surroundings and has receptors for it. When bacteria are few, the signal diffuses away and stays at a low concentration. As the population grows, the concentration rises. Once it passes a threshold, enough ligand binds to receptors to switch on particular genes in all the bacteria at once, so the population acts together.

Vibrio fischeri is a marine bacterium that lives in the light organ of the Hawaiian bobtail squid. A few free-living bacteria in seawater produce no light — it would be a waste of energy. Packed at high density inside the squid’s light organ, the autoinducer reaches the threshold, the genes for the light-producing enzyme luciferase are transcribed, and the bacteria glow. The squid uses the light, matched to moonlight from above, to hide its shadow from predators below; the bacteria get nutrients and a home.

Categories of signalling chemicals in animals

Hormones
Secreted by endocrine glands into the blood and carried to target cells anywhere in the body. Effects are often slower and longer-lasting. Examples: insulin, adrenaline, oestradiol.
Neurotransmitters
Released by neurons at synapses, diffusing a tiny distance to the next cell. Very rapid, short-lived effects. Examples: acetylcholine, dopamine.
Cytokines
Small proteins released by many cell types, especially immune cells, acting on nearby cells to regulate immune responses, inflammation and cell growth. Example: interleukins.
Calcium ions
Act as a signal inside cells. A sudden rise in Ca2+ concentration in the cytoplasm triggers events such as neurotransmitter release, muscle contraction or the cortical reaction in an egg.

Chemical diversity of hormones and neurotransmitters

A wide range of different substances is used as signals. One reason is that each signal must be distinct so that it binds only its own receptors; a large variety of shapes allows many separate messages to operate at once. Another is that different chemical types behave differently: some dissolve in blood, others pass through membranes; some are made quickly and broken down quickly, others last longer.

Hormones
Amines — small molecules derived from amino acids, e.g. adrenaline, thyroxine.
Proteins and peptides — e.g. insulin, ADH, FSH.
Steroids — derived from cholesterol, e.g. oestradiol, progesterone, testosterone.
Neurotransmitters
Amino acids — e.g. glutamate, GABA.
Peptides — e.g. endorphins.
Amines — e.g. dopamine, serotonin, noradrenaline.
A gas: nitric oxide (the guide’s wording is “nitrous oxide”), which diffuses freely across membranes.

Localized and distant effects

Neurotransmitters: localized
Diffuse across a synaptic gap of about 20 nm to receptors on one specific cell. The effect is fast, precise and brief, because the neurotransmitter is rapidly removed.
Hormones: distant
Transported by the blood system throughout the body, reaching every tissue, but act only on cells with receptors. The effect is slower, widespread and often longer lasting.

Transmembrane and intracellular receptors

Transmembrane receptors
Span the plasma membrane. The part embedded in the membrane is made of hydrophobic amino acids; the parts projecting outside and inside the cell are hydrophilic. The ligand binds on the outside and remains outside the cell. Used by hydrophilic signals that cannot cross the membrane: peptide hormones, amines, neurotransmitters.
Intracellular receptors
Located in the cytoplasm or nucleus. Hydrophilic proteins, since they are surrounded by water. The ligand must enter the cell, so it must be hydrophobic and able to diffuse through the membrane: steroid hormones.

Signal transduction

When a ligand binds to its receptor, the receptor changes shape. This sets off a sequence of responses inside the cell — a signal transduction pathway — that converts the external signal into an internal change such as opening a channel, activating enzymes, moving vesicles or switching genes on. Pathways often amplify the signal, so a few ligand molecules can have a large effect.

Neurotransmitter receptors that are ion channels

The acetylcholine receptor (at neuromuscular junctions and many synapses) is a transmembrane protein that is also an ion channel. When acetylcholine binds, the channel opens, allowing positively charged ions, mainly Na+, to diffuse into the cell. The inside becomes less negative, so the voltage across the membrane changes (depolarization). If it changes enough, this can trigger an action potential in the next neuron or contraction of a muscle fibre (C2.2).

G protein-coupled receptors

G protein-coupled receptors (GPCRs) are transmembrane receptors that pass the signal to a G protein attached to the inside of the membrane. Humans have hundreds of different GPCRs, for hormones, neurotransmitters, smells, tastes and light. The general mechanism:

  1. The ligand binds to the receptor on the outside of the cell, changing its shape.
  2. The receptor activates a G protein on the inside by causing it to release GDP and bind GTP.
  3. The activated G protein moves along the membrane and activates or inhibits an effector, usually an enzyme.
  4. The G protein then hydrolyses its GTP to GDP and becomes inactive again, ending the signal.

Adrenaline (epinephrine) and cAMP

Adrenaline cannot enter cells. It acts through a GPCR on target cells such as liver cells:

  1. Adrenaline binds to its receptor in the plasma membrane.
  2. The receptor activates a G protein.
  3. The G protein activates the enzyme adenylyl cyclase in the membrane.
  4. Adenylyl cyclase converts ATP into cyclic AMP (cAMP), the second messenger, which diffuses through the cytoplasm.
  5. cAMP activates an enzyme (a protein kinase), which sets off a cascade: in liver cells, enzymes that break down glycogen into glucose are activated, raising blood glucose for vigorous activity.

The hormone itself is the first messenger; cAMP carries the signal on inside the cell. Each step activates many molecules at the next step, so the signal is greatly amplified.

The two names are both in use. “Adrenaline” comes from Latin (ad, at; renes, kidneys) and “epinephrine” from Greek (epi, above; nephros, kidney), both referring to the adrenal glands above the kidneys. Unusually, both terms persist in different parts of the world, a reminder that naming conventions are an agreement among scientists.

Receptors with tyrosine kinase activity: insulin

The insulin receptor is a transmembrane protein that is itself an enzyme, a tyrosine kinase:

  1. Insulin binds to the receptor on the outside of the plasma membrane.
  2. The receptor changes shape, activating its tyrosine kinase domains on the inside, which add phosphate groups to tyrosine amino acids on the receptor (and on other proteins).
  3. The phosphorylated tyrosines are recognized by other proteins, starting a sequence of reactions inside the cell.
  4. The end result is that vesicles containing glucose transporters move to and fuse with the plasma membrane, inserting the transporters.
  5. Glucose enters the cell faster by facilitated diffusion, lowering blood glucose (D3.3).

Intracellular receptors and gene expression

Steroid hormones such as oestradiol, progesterone and testosterone are hydrophobic, so they diffuse through the plasma membrane.

  1. The hormone binds to a specific receptor protein in the cytoplasm or nucleus, activating it.
  2. The hormone–receptor complex (moving into the nucleus if needed) binds to specific DNA sequences near certain genes.
  3. This promotes transcription of those genes, so new proteins are made and the cell’s activity changes.

Because they work by changing gene expression, the effects of steroid hormones are usually slower to begin and longer lasting than those of hormones using membrane receptors.

Oestradiol and progesterone on target cells

Oestradiol → hypothalamus
Oestradiol acts on cells in the hypothalamus that secrete gonadotropin-releasing hormone (GnRH), altering GnRH secretion. GnRH controls the release of FSH and LH from the pituitary, so oestradiol regulates the menstrual cycle through this route (D3.1).
Progesterone → endometrium
Progesterone acts on cells of the endometrium (uterus lining), promoting expression of genes that maintain and thicken the lining, with more blood vessels and secretions, preparing it for implantation and maintaining pregnancy.

Positive and negative feedback

Negative feedback
The result of the signal reduces the signal, keeping a variable near a set level. Example: high blood glucose triggers insulin release; as glucose falls, insulin secretion decreases.
Positive feedback
The result of the signal increases the signal further, producing a rapid, amplifying change until an end point is reached. Example: in childbirth, oxytocin causes uterine contractions, which stimulate more oxytocin release, until the baby is born.

✏️Worked example

In a liver cell, one adrenaline molecule bound to its receptor activates about 100 G proteins over the time it is bound. Each G protein activates one adenylyl cyclase molecule, and each adenylyl cyclase produces about 1000 molecules of cAMP before it is switched off.
(a) Calculate the number of cAMP molecules produced per adrenaline molecule.
(b) Explain why this amplification is an advantage.
(c) Testosterone has no receptors in the plasma membrane of its target cells, but adrenaline does. Explain this difference in terms of the properties of the two hormones.

(a)

\[ 1 \times 100 \times 1000 = 100\,000\ \text{cAMP molecules} \]

(b) Hormones circulate at very low concentrations in the blood. Amplification means that binding of a very small number of hormone molecules to receptors can still produce a large, rapid response inside the cell — such as the breakdown of large amounts of glycogen during a fight-or-flight response. Further steps in the cascade (protein kinases activating many enzymes) amplify the signal even more.

(c) Adrenaline is an amine that is hydrophilic. It cannot diffuse through the hydrophobic core of the plasma membrane, so it must bind to a transmembrane receptor on the outside and act through a second messenger. Testosterone is a steroid, hydrophobic and lipid-soluble, so it diffuses through the membrane and binds to an intracellular receptor, which then acts on gene transcription.

Check it. Amplification multiplies at every stage, so the numbers are multiplied, not added: 100 + 1000 = 1100 would badly understate the effect. As a sanity check, a single hormone molecule producing a response involving tens of thousands of molecules is exactly the order of magnitude that makes hormones effective at nanomolar concentrations.
Saying adrenaline “enters the cell and activates enzymes”. Adrenaline never enters its target cell. It stays outside, bound to the receptor; the signal is carried inside by the G protein and cAMP. Only the steroid hormones on this page enter the cell. Keep the two pathways separate in every answer.

📝Practise

Work through these on paper, then reveal the answer. All are HL only.

1. Explain how quorum sensing allows Vibrio fischeri to produce light only when at high population density.
Each bacterium secretes a signalling molecule (autoinducer) and has receptors for it. At low density, the signal diffuses away and its concentration stays below the threshold, so light genes are not expressed. As the population grows (e.g. in the squid’s light organ), the concentration rises above the threshold, enough ligand binds to receptors, and transcription of genes for bioluminescence (luciferase) is switched on in all bacteria together. Light is produced only when there are enough bacteria for it to be useful, avoiding waste of energy.
2. Distinguish between hormones and neurotransmitters.
Hormones are secreted by endocrine glands into the blood and transported throughout the body, acting on distant target cells with the right receptors; their effects are generally slower, widespread and longer lasting. Neurotransmitters are released by neurons into a synaptic gap and diffuse a very short distance to receptors on one adjacent cell; their effects are fast, localized and brief because they are rapidly removed.
3. Compare transmembrane receptors with intracellular receptors.
Similarities: both are proteins with binding sites for specific ligands, and both initiate responses in the cell. Differences: transmembrane receptors are in the plasma membrane, with a hydrophobic region embedded in it, and bind hydrophilic ligands (e.g. insulin, adrenaline) that stay outside the cell; intracellular receptors are in the cytoplasm or nucleus, are hydrophilic, and bind hydrophobic ligands (steroids) that enter the cell. Transmembrane receptors act through channels, G proteins or kinases; intracellular receptors typically bind DNA and alter gene transcription directly.
4. Outline the mechanism of action of adrenaline on a liver cell.
Adrenaline binds to a G protein-coupled receptor in the plasma membrane. The receptor changes shape and activates a G protein (which binds GTP). The G protein activates adenylyl cyclase, which converts ATP into cyclic AMP, the second messenger. cAMP activates a protein kinase, which starts a cascade that activates the enzyme that breaks down glycogen into glucose. Glucose is released into the blood. The signal is amplified at each step.
5. Explain how insulin binding to its receptor increases glucose uptake by a muscle cell.
Insulin binds to the insulin receptor, a transmembrane protein with tyrosine kinase activity. Binding activates the kinase, which phosphorylates tyrosine residues on the inside of the receptor. This triggers a sequence of reactions within the cell, ending with vesicles containing glucose transporter proteins moving to the plasma membrane and fusing with it by exocytosis. More glucose transporters in the membrane allow glucose to enter the cell faster by facilitated diffusion.
6. Explain how progesterone affects cells of the endometrium.
Progesterone is a steroid, so it is hydrophobic and diffuses through the plasma membrane of endometrial cells. It binds to a specific intracellular receptor, activating it. The activated hormone–receptor complex binds to specific DNA sequences, promoting transcription of particular genes. The resulting proteins cause the endometrium to be maintained and thickened — with more blood vessels and glandular secretion — preparing it for implantation of an embryo and sustaining it during pregnancy.

🔗Go deeper — other people’s work

These are external resources, not mine. If one stops working, tell me and everything above it on this page still stands.

  • HHMI BioInteractive — the short film on bobtail squid and Vibrio fischeri quorum sensing.
  • RCSB Protein Data Bank, Molecule of the Month — G proteins, the insulin receptor and the acetylcholine receptor.
  • Khan Academy — Cell signalling, covering second messengers and receptor types.