Cell Signalling — Receptors, Second Messengers and Signal Cascades

Multicellular organisms need coordination. A liver cell must know when to release glucose; an immune cell must know when a pathogen has arrived. Signalling molecules (ligands) carry that information between cells — but the signal is only meaningful if the receiving cell has the right receptor.

Key principle: specificity is determined by the receptor, not the signal. The same hormone (e.g. adrenaline) can trigger different responses in heart vs. liver cells because they express different receptor types.

1. Cell-Surface Receptors (hydrophilic ligands)

Used by: peptide hormones (insulin, glucagon, ADH), catecholamines (adrenaline), most growth factors.

These ligands cannot cross the hydrophobic lipid bilayer, so they bind receptors on the cell surface.

Three main families:

a) G-protein Coupled Receptors (GPCRs) — largest family

• 7 transmembrane helices
• Binding of ligand activates an associated G-protein (Gαβγ trimer)
• Gα exchanges GDP for GTP → dissociates → activates downstream effector
• Most common effector: adenylyl cyclase → converts ATP to cAMP (second messenger)
• cAMP activates Protein Kinase A (PKA) → phosphorylates target proteins

Example: adrenaline → β-adrenergic receptor (GPCR) → cAMP → PKA → glycogen phosphorylase activated → glycogen broken down → blood glucose rises

b) Receptor Tyrosine Kinases (RTKs)

• Single transmembrane domain
• Ligand binding causes dimerisation → each monomer phosphorylates the other (cross-phosphorylation)
• Phosphorylated tyrosines on the cytoplasmic tail become docking sites for signalling proteins
• Activates RAS → MAP kinase cascade → gene expression changes

Example: Insulin receptor (an RTK) → activates PI3K → AKT pathway → GLUT4 transporters move to membrane → glucose uptake

c) Ligand-gated Ion Channels (ionotropic receptors)

• Fastest response (~milliseconds)
• Binding opens a channel directly — no second messenger needed
• Example: nicotinic acetylcholine receptor at NMJ → opens Na⁺ channel → depolarisation

2. Intracellular Receptors (hydrophobic ligands)

Used by: steroid hormones (testosterone, oestrogen, cortisol), thyroid hormone, vitamin D, and retinoic acid.

These ligands are lipid-soluble → cross the membrane → bind receptors in the cytoplasm or nucleus.

Mechanism:

1. Ligand diffuses into cell
2. Binds nuclear receptor (may displace inhibitory heat-shock proteins)
3. Ligand–receptor complex enters nucleus (or was already there)
4. Binds hormone response elements (HREs) on DNA
5. Recruits transcription machinery → changes gene expression

Slower effect (hours–days) but longer lasting than surface-receptor signalling (seconds–minutes).

The PLC–IP₃–DAG Pathway

1. GPCR or RTK activates Phospholipase C (PLC)
2. PLC cleaves PIP₂ (membrane lipid) into IP₃ and DAG
3. IP₃ opens Ca²⁺ channels on the ER → cytoplasmic Ca²⁺ spikes
4. Ca²⁺ binds calmodulin → activates many kinases
5. DAG stays in membrane → activates PKC

One hormone → one receptor → 100 G-proteins → 1000 cAMP molecules → 10,000 PKA activations → 100,000 enzyme molecules affected.

This is why hormones work at nanomolar concentrations.

Caffeine inhibits PDE → cAMP stays high → adenosine signal is blunted.

• Steroid hormones → intracellular receptors → gene expression (slow, long-lasting)
• Peptide/amine hormones → cell-surface receptors → second messengers (fast, short)
• cAMP: made by adenylyl cyclase, degraded by PDE, activates PKA
• RTKs dimerize and cross-phosphorylate — insulin receptor is the NEET example
• G-protein: Gα is a GTPase — self-inactivating when GTP → GDP
• Signal amplification: 1 ligand → thousands of effector activations
• Desensitisation via β-arrestin prevents receptor lock-on