the stimulus-response model and the role of signalling molecules, receptors and signal transduction in coordinating cellular responses, including the role of apoptosis as a regulated cellular response

What this dot point is asking

VCAA wants the stimulus-response model applied to cells, the role of signalling molecules and receptors (with the hydrophilic vs hydrophobic split), the meaning of signal transduction, and the role of apoptosis as a regulated cellular response (compared with necrosis), including examples in development and disease.

The answer

Cells coordinate behaviour through chemical signals. A signalling cell releases a signalling molecule, which binds a receptor on a target cell and triggers a response. This sequence is an application of the stimulus-response model at the cellular level.

The stimulus-response model in cells

1. Stimulus. A change in the internal or external environment of the organism (for example, blood glucose rising, an immune trigger, a developmental cue).
2. Reception. The signalling molecule binds a specific receptor on or inside the target cell.
3. Transduction. The binding event is converted, often through a cascade, into changes inside the cell.
4. Response. The cell changes its behaviour: opens or closes channels, activates or inhibits enzymes, alters gene expression, divides, or undergoes apoptosis.

Signalling molecules

Signalling molecules include hormones (insulin, adrenaline, oestrogen, testosterone), neurotransmitters (acetylcholine, dopamine), cytokines (in immune responses) and growth factors. They fall into two broad classes based on solubility.

Hydrophilic (water-soluble) signalling molecules. Examples: peptide and protein hormones (insulin, glucagon, adrenaline), most neurotransmitters. They cannot cross the phospholipid bilayer, so they bind surface receptors on the plasma membrane.

Hydrophobic (lipid-soluble) signalling molecules. Examples: steroid hormones (oestrogen, testosterone, cortisol), thyroid hormone, vitamin D. They diffuse straight through the membrane and bind intracellular receptors in the cytosol or nucleus. The activated receptor-hormone complex usually acts as a transcription factor, changing which genes are expressed.

Receptors

A receptor is a protein with a binding site specific to one signalling molecule (or a small family of related molecules). Binding is reversible and complementary in shape and chemistry, like an enzyme-substrate fit.

• Surface receptors sit in the plasma membrane and bind hydrophilic signals on the outside. Major types include G-protein coupled receptors, receptor tyrosine kinases, and ligand-gated ion channels.
• Intracellular receptors sit in the cytosol or nucleus and bind hydrophobic signals that have crossed the membrane.

Target specificity arises because only cells expressing the matching receptor can respond.

Signal transduction

Signal transduction is the chain of events between receptor binding and the cellular response. A surface receptor cannot directly change cytoplasmic enzymes or gene expression, so it triggers a cascade of intracellular messengers.

Typical features include:

• Conformational change in the receptor on binding.
• Second messengers such as cyclic AMP (cAMP), Ca2+ or inositol triphosphate (IP3) that diffuse inside the cell.
• Protein kinases that phosphorylate downstream proteins, activating or inactivating them.
• Amplification. One signalling molecule can trigger thousands of intracellular events because each step activates many molecules of the next.
• Termination. Phosphatases and second-messenger breakdown switch the signal off.

For hydrophobic signals, transduction is shorter: the receptor-hormone complex binds DNA directly and changes transcription.

Apoptosis: regulated cell death

Apoptosis is a controlled, programmed sequence of events that dismantles a cell from within. It is triggered when receptors detect signals such as DNA damage, viral infection, withdrawal of growth factors, or developmental cues.

Process.

1. Internal or external signals activate initiator caspases (proteases).
2. Initiator caspases activate executioner caspases.
3. Executioner caspases cleave key cellular targets: the cytoskeleton collapses, the nuclear lamina breaks down, endonucleases fragment DNA into regular pieces.
4. The cell shrinks and the plasma membrane forms blebs.
5. The cell breaks into apoptotic bodies, sealed membrane-bound packages.
6. Macrophages engulf the apoptotic bodies. Cell contents are not released, so there is no inflammation.

Apoptosis vs necrosis.

Role in development. Apoptosis sculpts tissues during embryonic development. The webbing between fingers and toes in the human embryo is removed by apoptosis. Tadpole tails resorb in the same way. Excess neurons that fail to make functional connections are pruned during brain development.

Role in disease and homeostasis. Apoptosis removes:

• Cells with irreparable DNA damage (preventing cancer).
• Virus-infected cells (limiting spread).
• Self-reactive immune cells (preventing autoimmunity).

When apoptosis fails, damaged cells survive and can become cancerous. When apoptosis is excessive or misfired, healthy cells are lost, contributing to neurodegenerative diseases such as Alzheimer's and Parkinson's, and to tissue damage in heart attack and stroke.

Examples in context

Example 1. Insulin signal transduction at WEHI. WEHI diabetes researchers map insulin's signal pathway. Insulin (the signalling molecule) binds the insulin receptor on liver-cell plasma membrane. The receptor's intracellular tyrosine-kinase domain autophosphorylates, then phosphorylates insulin-receptor substrate proteins. A cascade activates PI3-kinase, then Akt, which triggers translocation of GLUT4 transporters to the membrane so glucose enters the cell. The stimulus (high blood glucose) produces the response (glucose uptake) via membrane receptor, second messengers and effector proteins - the textbook stimulus-response model. Insulin resistance, the basis of type 2 diabetes, arises when this pathway is dampened by chronic high insulin and metabolic stress.

Example 2. CAR-T apoptosis induction at Peter MacCallum. Peter MacCallum's CAR-T cell therapy demonstrates apoptosis as a regulated cellular response. Engineered T cells recognise CD19 on lymphoma cells via the chimeric antigen receptor. Binding triggers T-cell release of perforin (which forms pores in target membrane) and granzymes (which enter through pores). Granzyme B activates caspase-8 inside the lymphoma cell, then caspase-3, which cleaves hundreds of substrates including the inhibitor of caspase-activated DNase, releasing CAD to fragment DNA. The cell shrinks, blebs into apoptotic bodies, and is cleared by phagocytes without inflammation. This is a clean immunological execution, contrasted with the messy necrosis caused by chemotherapy.

Try this

Q1. Outline the stimulus-response model with reference to signalling molecule, receptor and effector response. [3 marks]

• Cue. Stimulus is detected as a signalling molecule binding a specific receptor; signal transduction relays the message into the cell; effector proteins produce the response.

Q2. A patient's liver cells lose insulin receptor function due to a genetic mutation. Predict the effect on blood glucose after a meal and explain. [3 marks]

• Cue. Without functional receptor, insulin cannot trigger GLUT4 translocation; glucose remains in blood; hyperglycaemia (insulin resistance, similar to type 2 diabetes).

Q3. Refer to apoptosis in CAR-T therapy. (a) Identify the trigger of caspase-8 activation. (b) Describe two morphological changes in the dying cell. (c) Compare apoptosis with necrosis in terms of inflammation. [2+2+2 marks]

• Cue. (a) Granzyme B (delivered by CAR-T cell via perforin pores). (b) Cell shrinkage, membrane blebbing, chromatin condensation (any two). (c) Apoptosis is non-inflammatory; necrosis releases cell contents and triggers inflammation.