C2.1 Chemical signalling [HL only]

Chemical signalling coordinates cell responses through ligands, receptors and transduction pathways that convert external or internal signals into specific physiological effects.

Learning objectives

C2.1.1(HL)—Receptors as proteins• Receptor proteins have binding sites specific to signalling ligands• Ligand binding starts signal transduction in target cells C2.1.2(HL)—Quorum sensing in bacteria• Autoinducers allow bacteria to detect population density thresholds• Vibrio fischeri bioluminescence and biofilm formation are key examples C2.1.3(HL)—Functional categories in animals• Animal signals include hormones, neurotransmitters, cytokines, and Ca²⁺ ions• They differ in source, distance, speed, and target-cell response C2.1.4(HL)—Chemical diversity• Hormones include protein/peptide, steroid, and amine classes• Neurotransmitters include acetylcholine, amino acids, peptides, amines, and nitric oxide C2.1.5(HL)—Localized vs. distant effects• Neurotransmitters act locally across narrow synaptic clefts• Hormones travel through blood to distant cells with matching receptors C2.1.6(HL)—Transmembrane vs. intracellular receptors• Hydrophilic ligands bind transmembrane receptors and use intracellular relays• Steroid and thyroid hormones cross membranes and bind cytoplasmic or nuclear receptors C2.1.7(HL)—Signal transduction pathways• Signal transduction relays, amplifies, integrates, and distributes ligand signals• Pathways use relay proteins, second messengers, phosphorylation cascades, and effectors C2.1.8(HL)—Neurotransmitter receptors and membrane potential• Acetylcholine can bind ligand-gated sodium channels• Sodium influx changes membrane potential and can depolarize the postsynaptic membrane C2.1.9(HL)—G protein-coupled receptors• GPCRs are seven-helix transmembrane receptors linked to G proteins• Ligand binding causes GDP-GTP exchange and activation of effector proteins C2.1.10(HL)—Epinephrine (adrenaline) mechanism• Epinephrine binds adrenergic GPCRs and activates G protein signalling• Adenylyl cyclase forms cAMP, activating kinase cascades for glycogen breakdown C2.1.11(HL)—Tyrosine kinase receptors• RTK ligand binding causes dimerisation and autophosphorylation• Insulin signalling moves GLUT4 vesicles to membranes and promotes glycogenesis C2.1.12(HL)—Intracellular receptors• Steroid and thyroid hormones bind intracellular receptor proteins• Hormone-receptor complexes enter or act in the nucleus as transcription factors C2.1.13(HL)—Effects of oestradiol and progesterone• Oestradiol regulates female sex characteristics and hypothalamus-pituitary targets• Progesterone from corpus luteum or placenta maintains endometrium and pregnancy C2.1.14(HL)—Regulation by feedback• Positive feedback amplifies responses, such as ethylene in fruit ripening• Negative feedback restores stability, such as insulin lowering blood glucose

A ligand is a signalling molecule that binds to a specific site on a receptor protein. Complementary shape and chemical interactions make the binding selective.

A ligand starts an intracellular relay only in the cell whose receptor has a matching binding site.

A signal may reach many cells, but only cells with the matching receptor are target cells. Binding changes receptor conformation and initiates signal transduction; it does not itself guarantee the same response in every target cell.

In quorum sensing, bacteria release autoinducers and detect their extracellular concentration. Autoinducer concentration therefore carries information about population density.

Low density: autoinducers diffuse away, so receptors are rarely activated.
Rising density: production exceeds loss and concentration increases.
Threshold reached: receptor activation changes transcription in many cells together.
Positive feedback can increase autoinducer synthesis and sharpen the switch.

Signal molecules remain dilute at low bacterial density but accumulate at high density, where coordinated group behaviour begins.

Quorum sensing delays costly cooperative behaviours until a dense population can produce an effective combined output.

Behaviour	Why a density threshold matters
Vibrio fischeri bioluminescence	luciferase production is energy-intensive; a dense population produces visible light that benefits the squid host and therefore the bacteria
Pseudomonas aeruginosa biofilm	many cells together secrete a protective extracellular matrix and damaging enzymes; the biofilm can increase resistance to stress and antibiotics

If each isolated cell acted alone, the product would be too dilute to achieve the group effect. The threshold links individual sensing to population-level efficiency.

Functional category	Typical source and route	Main role
hormone	endocrine cell or gland; usually carried in blood	coordinate distant target tissues
neurotransmitter	presynaptic neuron; released across a synaptic cleft	rapidly signal a nearby neuron, muscle or gland cell
cytokine	many cell types; usually acts locally	alter growth, differentiation, immune activity or behaviour of nearby cells
Ca²⁺ ion	enters cytosol or is released from intracellular stores	acts as an intracellular second messenger

Four animal signalling routes: hormone through blood, neurotransmitter across a synapse, cytokine to a nearby cell, and calcium ions acting inside a cell.

A functional label does not uniquely specify chemical structure: epinephrine can act as a hormone or neurotransmitter, while Ca²⁺ is an inorganic ion rather than an organic molecule.

Hormone class	Examples	Membrane consequence
protein or peptide	insulin, glucagon	water-soluble; binds a cell-surface receptor
amine	epinephrine, thyroid hormones	properties vary: epinephrine is water-soluble; thyroid hormones are lipid-soluble
steroid	oestradiol, progesterone, testosterone	lipid-soluble; crosses the membrane

Neurotransmitters include acetylcholine, amino acids such as GABA, peptides such as endorphins, amines such as dopamine, and the gas nitric oxide. This chemical diversity prevents a single structure-based definition.

To predict a signalling route, use solubility and charge, not the label ‘hormone’ or ‘neurotransmitter’ alone.

Feature	Synaptic signalling	Endocrine signalling
delivery	diffusion across a 20–40 nm cleft	transport in blood
initial range	highly local	body-wide distribution
responding cells	postsynaptic cells with matching receptors	any reached cell with matching receptors
typical timing	rapid and brief	usually slower and longer-lasting

A hormone can pass many non-target cells without affecting them. A neurotransmitter is released very close to its target, but still requires the correct receptor.

A neurotransmitter crosses a 20–40 nanometre synaptic cleft, while a hormone travels in blood and activates only a distant cell with a matching receptor.

Recognition: ask which receptor binds the ligand and therefore which cells can respond.

Classification: distinguish functional category from chemistry. A signal's name or role alone does not determine its solubility, receptor location or exact response.

Evidence	Best interpretation
concentration rises with bacterial density and crosses a threshold	quorum sensing by an autoinducer
released by a neuron across a 20–40 nm gap	neurotransmitter; local synaptic signalling
secreted into blood and acts on distant receptor-bearing cells	hormone; endocrine signalling
released by a cell and alters nearby immune or growth responses	cytokine; local signalling

Ligand property	Receptor	How the signal reaches an intracellular target
charged or water-soluble	transmembrane receptor	ligand stays outside; receptor conformational change starts a relay or opens a channel
non-polar and lipid-soluble	cytoplasmic or nuclear receptor	ligand diffuses through the bilayer; ligand–receptor complex regulates target proteins or genes

Peptide hormones such as insulin use cell-surface receptors. Steroid hormones and thyroid hormones use intracellular receptors. Receptor location follows membrane permeability, not signalling distance.

A water-soluble ligand binds a transmembrane receptor and uses an intracellular relay, while a lipid-soluble ligand crosses the membrane and binds an intracellular receptor that regulates transcription.

Cell signalling follows three broad stages: ligand–receptor interaction → signal transduction → cellular response.

Relay: pass information between molecular components.
Amplify: one activated component activates many downstream molecules.
Integrate: combine inputs from more than one pathway before deciding an output.
Distribute: branch one signal toward several effectors and responses.

Second messengers such as cAMP or Ca²⁺ spread signals through the cytoplasm. Protein kinases add phosphate groups and phosphatases remove them, creating reversible molecular switches.

Acetylcholine binds to sites on the postsynaptic receptor.
The receptor changes conformation and its aqueous pore opens.
Na⁺ moves into the cell down its electrochemical gradient.
Positive charge makes the inside less negative: the postsynaptic membrane depolarises.
If threshold is reached, a new action potential can be initiated.

Acetylcholine supplies the gating signal; it does not carry Na⁺ through the membrane or provide the energy for diffusion.

Acetylcholine binds to a nicotinic receptor and opens its sodium-ion channel.

A G protein-coupled receptor (GPCR) has seven transmembrane α-helices and couples an extracellular ligand-binding event to an intracellular G protein.

Resting: the G protein holds GDP and is inactive.
Activation: ligand changes GPCR shape; GDP leaves and GTP binds.
Output: activated G-protein subunits bind effector proteins such as enzymes or ion channels.
Shut-off: intrinsic GTPase hydrolyses GTP to GDP, ending effector activation and resetting the switch.

A ligand-bound seven-helix GPCR promotes exchange of GDP for GTP on the G protein, whose subunits then activate effectors.

epinephrine → adrenergic GPCR → Gs protein → adenylyl cyclase → ATP converted to cAMP → PKA → phosphorylase kinase → glycogen phosphorylase → glycogen breakdown

Epinephrine activates an adrenergic GPCR, a G protein, adenylyl cyclase, cAMP, PKA and a kinase cascade that promotes glycogen breakdown.

Amplification occurs because each active component can generate or activate many molecules at the next step. The cell rapidly releases glucose 1-phosphate without waiting for new gene expression.

Phosphodiesterase converts cAMP to AMP, protein phosphatases reverse phosphorylation, and GTP hydrolysis switches off the G protein. A strong response must still be terminable.

Route	Direct intracellular event	Amplification	Representative output
ligand-gated channel	pore opens	little within the receptor step	rapid membrane-potential change
GPCR	G protein exchanges GDP for GTP	effectors and second messengers can multiply the signal	ion-channel control or enzyme cascade
epinephrine GPCR	adenylyl cyclase makes cAMP	cAMP and kinase cascade strongly amplify	rapid glycogen breakdown

All three begin with a specific extracellular ligand and a transmembrane receptor. The receptor's structure determines whether the first intracellular event is ion flow, G-protein activation or another relay.

When diagnosing an unfamiliar pathway, locate the receptor, identify the first intracellular change, trace any amplification, name the effector response, and find the shut-off step.

A receptor tyrosine kinase (RTK) has an extracellular ligand-binding region, one transmembrane α-helix and an intracellular kinase domain containing tyrosine residues.

Ligand binding brings two receptor monomers together.
Dimerisation positions the kinase domains beside one another.
Each kinase transfers phosphate groups from ATP to tyrosines on the other receptor: autophosphorylation.
Phosphorylated sites recruit and activate specific relay proteins.
Different relay proteins can launch several pathways from the same receptor complex.

Unlike a GPCR, the receptor itself has enzyme activity. Unlike a ligand-gated channel, activation does not directly open a pore.

Activated relay proteins move GLUT4-containing vesicles to the plasma membrane.
Vesicle fusion inserts more GLUT4 transporters, increasing glucose uptake in muscle and adipose cells.
The pathway also activates glycogen synthase, promoting glycogenesis.
In liver, insulin promotes glucose storage and suppresses glucose production, although liver glucose entry is not via GLUT4.

Insulin activates its receptor tyrosine kinase, causing autophosphorylation, a kinase pathway, GLUT4-vesicle fusion, glucose uptake and glycogen synthesis.

As blood glucose falls toward its set range, pancreatic insulin secretion decreases. The response removes the original stimulus, so this is negative feedback.

lipid-soluble hormone diffuses through the plasma membrane → binds a cytoplasmic or nuclear receptor → receptor changes conformation → hormone–receptor complex enters or acts within the nucleus → complex binds a regulatory DNA sequence → transcription of specific genes changes

The activated receptor acts as a transcription factor. New mRNA can direct synthesis of proteins that change cell structure or metabolism; repression of transcription can stop a process.

Lipid solubility allows the hormone to enter many cells, but only cells containing the correct intracellular receptor respond. Steroid and thyroid hormones use this general route.

Membrane-initiated cascade	Intracellular-receptor pathway
modifies existing proteins and can be very rapid	changes transcription and usually develops more slowly
ligand usually remains outside the cell	ligand crosses the plasma membrane
second messengers may amplify the signal	receptor–ligand complex directly regulates DNA transcription

Hormone	Main source	Important target effects
oestradiol	mainly growing ovarian follicles; also placenta and other tissues	develops and maintains female sex characteristics; acts on uterus, breasts, bone and hypothalamus–pituitary control
progesterone	corpus luteum after ovulation; placenta later in pregnancy	prepares and maintains the endometrium; supports pregnancy and helps prevent further ovulation

If implantation does not occur, the corpus luteum degenerates, progesterone falls and the endometrium is no longer maintained. If pregnancy occurs, progesterone secretion continues and the placenta later becomes the major source.

Both are lipid-soluble steroid hormones. Their different effects reflect receptor distribution, regulated genes and tissue context—not a different basic receptor mechanism.

Feedback	Effect of the response	System behaviour
positive	reinforces the initiating change	moves further from the starting state; can create a switch-like response
negative	opposes the initiating change	returns a regulated variable toward its set range and promotes stability

Ethylene and fruit ripening: ethylene promotes ripening; ripening tissue releases more ethylene, so neighbouring tissue ripens and the response accelerates.
Insulin and blood glucose: high glucose stimulates insulin; insulin increases uptake and storage, lowering glucose and therefore reducing the stimulus for further insulin release.
Quorum sensing: once the autoinducer threshold is crossed, increased autoinducer production can reinforce population-wide activation.

Classify feedback by asking what the response does to the original change. ‘Positive’ does not mean beneficial, and ‘negative’ does not mean harmful.

1 Select: identify the ligand, its route, its solubility and the cells that carry the matching receptor.

2 Transduce: locate the receptor, then trace the first intracellular event—ion flow, GDP–GTP exchange, RTK autophosphorylation or direct gene regulation. Mark where the signal is relayed, amplified, integrated or branched.

3 Respond and reset: name the effector change, then identify termination or feedback. A complete explanation links molecular events to the cell or organism response and explains why the response stops, stabilises or accelerates.

Clue	Likely route
ACh opens Na⁺ channel	ligand-gated receptor → depolarisation
seven membrane helices and GDP/GTP switch	GPCR → effector protein
receptor dimerisation and phosphorylated tyrosines	RTK → relay proteins
lipid-soluble ligand and altered transcription	intracellular receptor → DNA regulation

4 marks

Describe, with examples, the types of molecule within cell-to-cell signalling systems that are complementary to each other.

4 marks

B. subtilis colonies form biofilms through quorum sensing.
(i) Define quorum sensing.
(ii) State three possible advantages to B. subtilis of forming a biofilm.
1.
2.
3.

7 marks

Compare and contrast hormonal and nervous communication.

2 marks

State one example of a steroid hormone and one example of a protein hormone.

Steroid hormone:

Protein hormone:

1 mark

Leptin is a hormone. Hormones are chemicals produced in one part of the body that have an effect in another part of the body. State the target that leptin normally acts on.

6 marks

Compare and contrast the mode of action of peptide hormones and steroid hormones.

3 marks

Heart rate is affected by the hormone epinephrine. The action of epinephrine is mediated by a chemical called a second messenger. Explain the mechanism of action of a second messenger.

1 mark

Atropine drops are used by opticians to dilate the pupil, so that a thorough examination of the retina can be performed. Atropine binds to acetylcholine receptors in synapses.

What is the effect of atropine binding in synapses?

3 marks

Explain how epinephrine exerts its effects in the cell.

1 mark

What is an example of negative feedback in the menstrual cycle?

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—C2.2 Neural signallingRead

C2.1 Chemical signalling [HL only]

Learning objectives

A Signal Selects Its Target by Receptor Fit

Quorum Sensing Turns Cell Density into a Shared Decision

Group Behaviours Pay Off Only When Enough Bacteria Join

Animal Signals Are Classified by How They Work

Function Does Not Reveal a Signal's Chemistry

Distance Changes Delivery, Not Target Specificity

Checkpoint: Identify the Signal Before Following the Pathway

Ligand Solubility Predicts Receptor Location

Transduction Processes Information, Not Just Passes It On

A Ligand-Gated Channel Converts Chemistry into Voltage

A GPCR Controls a Reversible GTP Switch

Epinephrine Amplifies a Signal through cAMP

Checkpoint: Membrane Receptors Produce Different Kinds of Speed

An RTK Builds a Phosphorylated Signalling Platform

Insulin Signalling Increases Uptake and Storage of Glucose

Intracellular Receptors Convert a Ligand into Gene Regulation

Oestradiol and Progesterone Coordinate Different Targets

Feedback Controls Whether a Signal Fades or Reinforces Itself

Summary: Diagnose Any Chemical-Signalling Pathway

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