C2.1 Chemical signalling [HL only]

A receptor is a protein with a binding site specific to a signalling chemical, called a ligand.

Complementary shape and chemical interactions allow a ligand to bind selectively. Binding changes the receptor's state or conformation and initiates a sequence of responses inside the target cell.

Identify four linked parts: ligand → specific receptor binding site → receptor activation → intracellular response. A cell is a target only if it has the appropriate receptor.

Insulin can circulate past many cells, but only cells expressing an insulin receptor bind it and initiate the corresponding signal-transduction pathway.

Specific does not mean that a receptor completes the response by itself. It detects its ligand and starts a pathway; downstream cell machinery produces the response.

Quorum sensing allows bacteria to coordinate gene expression by releasing and detecting signalling molecules whose concentration indicates local population density.

Each cell releases an autoinducer. At low density it diffuses away, but as population density rises its local concentration increases; once a threshold is reached, receptor activation switches on coordinated genes.

Sequence: autoinducer release → concentration rises with cell density → threshold detection → coordinated gene expression across the bacterial population.

The marine bacterium Vibrio fischeri produces bioluminescence only when a dense population in its host's light organ accumulates enough autoinducer to cross the quorum threshold.

Quorum sensing estimates local density through chemical concentration; it is not nervous communication. Dilution or flow can prevent threshold activation even when bacteria are present.

Animal chemical signals differ in source, distance, speed and target-cell effect. Hormones are released by endocrine cells into blood and act at distant targets, usually more slowly. Neurotransmitters are released by neurons across synapses and act rapidly on nearby target cells. Cytokines are released by immune and other cells and coordinate local or systemic responses. Ca²⁺ ions act as short-lived intracellular signals that regulate target proteins.

• Hormone: endocrine source; bloodstream; distant target; relatively slow and longer-lasting.
• Neurotransmitter: neuron; synaptic cleft; adjacent target; rapid response.
• Cytokine: immune or other cell; local or body-fluid signalling; coordinates immune responses.
• Ca²⁺: intracellular messenger; changes protein activity inside the responding cell.
• Hormones can be protein/peptide, steroid or amine; neurotransmitters include acetylcholine, amino acids, peptides, amines and nitric oxide.

A localized signal acts near its source, whereas an endocrine signal travels through circulation to distant target cells.

Paracrine and synaptic signals reach nearby cells with short delays and limited dilution. Endocrine hormones can reach the whole body but only cells with the correct receptor respond.

Locate the signal’s range:

• autocrine: same cell
• paracrine: nearby cells
• synaptic: across a synapse
• endocrine: distant through blood

A neurotransmitter acts across a tiny synaptic gap, while thyroxine circulates and affects distant tissues with thyroid-hormone receptors.

Circulation makes a signal widespread, not automatically effective in every tissue.

Whether a signalling ligand crosses the phospholipid bilayer determines whether it binds a transmembrane receptor or an intracellular receptor.

Oestradiol, progesterone and testosterone cross the membrane and bind intracellular receptors. The activated hormone–receptor complex binds specific DNA sequences and promotes transcription of target genes.

Receptor location follows ligand permeability and protein structure, not simply whether the signal is called a hormone. Protein hormones generally require surface receptors; steroid hormones use intracellular receptors.

Signal transduction is the chain of molecular events linking receptor activation to a change in cell behaviour.

The chain may include conformational changes, G proteins, kinases, second messengers, transcription factors and feedback. Amplification allows a few signal molecules to influence many targets.

Map a pathway:

• receptor state changes
• relay or second messenger activates
• target proteins or genes change
• response is terminated

One activated receptor can stimulate many downstream enzymes, amplifying a small external signal into a measurable metabolic response.

A pathway is not complete until the signal is switched off or degraded; otherwise the cell cannot respond accurately.

Acetylcholine binds a transmembrane receptor that is also a ligand-gated ion channel in the postsynaptic membrane.

Ligand binding changes the receptor's conformation and opens the channel. Positively charged ions diffuse into the postsynaptic cell down their electrochemical gradient, making the inside less negative and changing membrane potential.

Sequence: acetylcholine binds → receptor channel opens → positive ions enter → postsynaptic membrane depolarizes → the voltage change may trigger further events.

At a cholinergic synapse, opening acetylcholine-receptor channels produces a local depolarization; if combined depolarization reaches threshold, a postsynaptic action potential can follow.

Acetylcholine does not itself cross the membrane or carry charge into the cell. It opens a receptor channel; ion diffusion causes the voltage change.

A G protein-coupled receptor (GPCR) is a transmembrane receptor that conveys ligand binding into the cell by activating a membrane-associated G protein.

Ligand binding changes the receptor's conformation. The activated receptor promotes exchange of GDP for GTP on the G protein; an activated G-protein subunit then regulates an effector protein such as an enzyme or ion channel.

Many human receptors use this mechanism. Sequence: ligand binds GPCR → GDP is replaced by GTP on G protein → active subunit changes an effector → intracellular response follows.

A G-protein subunit can activate adenylyl cyclase, which generates the second messenger cAMP and thereby relays the external signal to intracellular targets.

The GPCR relays the signal without entering the cell. GTP is a switch on the G protein; it is not the extracellular ligand or the second messenger cAMP.

Adrenaline binds a GPCR and activates a cAMP pathway that rapidly promotes glycogen breakdown in target cells.

The receptor activates a stimulatory G protein, adenylyl cyclase makes cAMP, and a kinase cascade activates glycogen phosphorylase. Phosphodiesterase and receptor reset limit the response.

Follow the sequence:

• adrenaline binds receptor
• G protein activates adenylyl cyclase
• cAMP activates kinase
• glycogen becomes glucose units

One adrenaline molecule can trigger many cAMP molecules and therefore amplify glycogen breakdown during exercise.

Adrenaline does not directly split glycogen at the receptor; the kinase cascade mediates the response.

The insulin receptor is a transmembrane receptor with tyrosine kinase activity; insulin binding outside the cell causes phosphorylation of tyrosine residues inside the cell.

The phosphorylated receptor initiates a sequence of intracellular reactions. The syllabus endpoint is movement of vesicles containing glucose transporters to the plasma membrane.

Sequence: insulin binds receptor → intracellular tyrosines are phosphorylated → signalling reactions are activated → glucose-transporter vesicles move to and fuse with the plasma membrane → glucose uptake capacity increases.

In an insulin-responsive muscle or adipose cell, insertion of additional GLUT4 transporters increases facilitated diffusion of glucose from blood into the cell.

Insulin does not enter the cell or act as a glucose transporter. Keep this objective to receptor binding, tyrosine phosphorylation and transporter-vesicle movement; a Ras–MAP kinase growth-factor pathway is not the required example.

Oestradiol and progesterone are steroid hormones whose effects depend on intracellular receptors in specific target cells.

For oestradiol, the required target is receptor-containing cells in the hypothalamus that secrete gonadotropin-releasing hormone (GnRH). Oestradiol changes gene expression and thereby influences GnRH secretion.

For progesterone, the required target is receptor-containing cells in the endometrium. Progesterone-dependent gene expression maintains the endometrium in a state that can support pregnancy.

The same circulating hormone affects only cells with the matching receptor: hypothalamic GnRH-secreting cells respond to oestradiol, whereas endometrial cells are a specified target of progesterone.

Do not generalize these objectives to every reproductive effect of the hormones. The assessed target-cell examples are oestradiol in GnRH-secreting hypothalamic cells and progesterone in endometrium.

Feedback occurs when a response alters the signal pathway, either reducing further activation or amplifying it under defined conditions.

Negative feedback restores a variable toward a set range; positive feedback reinforces a change until a limiting event stops it. Receptors, hormones and downstream products can all participate.

Classify the loop:

• response opposes the original change: negative
• response reinforces it: positive
• identify the measured variable
• specify the stopping condition

Rising thyroid hormone suppresses hypothalamic and pituitary stimulation, whereas oxytocin-driven contractions can intensify until birth.

Calling any delayed response feedback is incomplete; the direction of the loop must be identified.