Curriculum
Module 08 · 75 min
Signal Transduction
GPCRs, RTKs, second messengers, and why most prescription drugs target signalling.
CoreClinicalResearch
Topics
What this module covers
- 01Receptor classes: GPCR, RTK, cytokine (JAK-STAT), TLR, nuclear
- 02Second messengers: cAMP, cGMP, Ca2+, IP3/DAG, NO, lipids
- 03Kinase cascades: MAPK (Ras/Raf/MEK/ERK), PI3K/Akt/mTOR, JAK/STAT
- 04GPCR biased agonism, β-arrestin signalling
- 05Receptor desensitisation, internalisation, recycling
- 06Crosstalk and feedback — why monotherapy fails predictably
Deep dives
Lesson sub-pages
Learning objectives
By the end of this module you will be able to
- L01Trace any approved targeted therapy (a kinase inhibitor, a JAK inhibitor, a SERD) to the node it perturbs.
- L02Explain biased agonism and one therapeutic implication.
- L03Predict resistance mechanisms for a given pathway block.
Expected takeaways
What you should walk away believing
- →≈30% of FDA-approved drugs target GPCRs.
- →Resistance to MAPK or EGFR blockade arises predictably via gatekeeper mutations or bypass tracks.
- →PI3K/Akt/mTOR integrates growth-factor and nutrient signals — the rationale for rapamycin in transplantation, oncology, and ageing trials.
Core summary
At the Core level
Cells decide what to do via signal transduction: ligand binds receptor → conformational change → cascade → transcriptional or cytoskeletal output. The same logic — kinase phosphorylates substrate, GTPase switches state, second messenger amplifies — recurs across pathways. Drugs that hit one node almost always have downstream and lateral consequences.
Myth vs reality
Common misconception
Claim
All agonists at one receptor produce the same downstream signalling.
Reality
Biased agonists preferentially engage G-protein vs β-arrestin pathways — exploited (intended) for safer opioids (oliceridine) and (unintended) in adverse-effect profiles.
Evidence-graded claims
Claims, scored A–F
A
Ras was 'undruggable' for 40 years
Until KRAS G12C inhibitors (sotorasib, adagrasib).
C
Biased agonism produces clinically meaningful safety differences
Theoretical strong; oliceridine modestly so in trials.
F
All TKIs work indefinitely
Resistance is the rule; sequencing is the strategy.
Quiz
Check your understanding
Q1. Imatinib resistance most commonly arises from:
Q2. Rapamycin inhibits primarily:
Flashcards
Lock it in
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Front
MAPK cascade order?
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Suggested reading
Primary literature
- Beyond the ligand: extracellular and transcellular G protein–coupled receptor signaling — Heuberger & Roth, Annu Rev Pharmacol 2019 ↗
- KRAS(G12C) inhibition with sotorasib — Hong et al., NEJM 2020 ↗