Cell Signaling & Second Messengers
How the boards test cell signaling: match each receptor to its G protein (Gs/Gi/Gq) and second messenger, work the cAMP/IP₃-DAG/cGMP-NO/RTK/JAK-STAT/nuclear pathways, and recognize the classic toxins and GNAS diseases (cholera, pertussis, McCune-Albright) that hijack them.
Big picture: signal in, response out
Cell signaling converts an extracellular ligand into an intracellular response. Water-soluble ligands (peptides, catecholamines) bind surface receptors and act through second messengers; lipid-soluble ligands (steroids, thyroid hormone) cross the membrane to reach intracellular/nuclear receptors that directly alter gene transcription. Second messengers — cAMP, cGMP, IP₃, DAG, Ca²⁺ — amplify: one activated receptor spawns many messenger molecules that switch on kinases (PKA, PKC, PKG) which phosphorylate downstream targets. Step 1 tests three things relentlessly: which G protein a receptor couples to (Gs, Gi, Gq), which second messenger results, and the classic toxins/diseases that hijack the pathway (cholera, pertussis, McCune-Albright). Learn the receptor → G protein → messenger → effect chain and most questions fall out directly.
- GPCRs = 7-transmembrane receptors coupled to trimeric G proteins (α/β/γ). Ligand binding drives GDP→GTP exchange on Gα → effector activation; intrinsic GTPase turns it off.
- Gs → ↑ adenylyl cyclase → ↑ cAMP → activates PKA.
- Gi → ↓ adenylyl cyclase → ↓ cAMP.
- Gq → phospholipase C-β → cleaves PIP₂ into IP₃ + DAG. IP₃ → ↑ intracellular Ca²⁺ (from ER); DAG (+ Ca²⁺) → PKC.
- cAMP is degraded by phosphodiesterase (PDE): caffeine/theophylline nonselectively inhibit PDE (↑cAMP); milrinone inhibits cardiac PDE-3 (↑cAMP, inodilator); sildenafil inhibits PDE-5 (↑cGMP).
- Amplification: one receptor → many G proteins → many cAMP → many phosphorylated targets.
Gs vs Gi vs Gq — the core comparison
| Feature | Gs | Gi | Gq |
|---|---|---|---|
| Enzyme | ↑ adenylyl cyclase | ↓ adenylyl cyclase | phospholipase C-β |
| 2nd messenger | ↑ cAMP → PKA | ↓ cAMP | IP₃ + DAG → ↑Ca²⁺, PKC |
| Key receptors | β1, β2, D1, H2, V2 | M2, α2, D2 | α1, M1, M3, H1, V1 |
| Classic toxin | cholera (locks ON) | pertussis (locks OFF) | — |
| Example effect | ↑ HR, glycogenolysis | ↓ HR (M2) | vasoconstriction (α1) |
- Receptor tyrosine kinases (RTKs): ligand → dimerization → autophosphorylation → RAS/MAP kinase and PI3K/Akt. Ligands: insulin, IGF-1, EGF, FGF, PDGF (insulin also → GLUT4 translocation via PI3K/Akt).
- JAK-STAT (non-receptor TK): cytokine binds → JAK phosphorylates → STAT dimerizes → nucleus. Ligands: GH, prolactin, EPO, TPO, G-CSF, leptin, most interleukins/interferons.
- cGMP / NO pathway: NO (endothelium-derived relaxing factor) → soluble guanylyl cyclase; ANP/BNP → membrane (particulate) guanylyl cyclase → ↑ cGMP → activates PKG → ↓ intracellular Ca²⁺ → smooth-muscle relaxation/vasodilation. Nitroglycerin & nitroprusside donate NO; sildenafil blocks cGMP breakdown (PDE-5).
- Intracellular (nuclear) receptors: lipophilic ligands — cortisol, aldosterone, estrogen, testosterone, progesterone, vitamin D, T3/T4 — directly regulate transcription (slow, hours–days).
Vignette: A traveler returns from an endemic region with profuse, painless "rice-water" stools and severe dehydration; stool has no blood or leukocytes.
Dx: Vibrio cholerae.
Mechanism (the tested point): Cholera toxin ADP-ribosylates the Gsα subunit, locking it ON → constitutive adenylyl cyclase → ↑↑ cAMP → PKA phosphorylates and opens CFTR → massive Cl⁻ and water secretion.
Contrast — pertussis toxin: ADP-ribosylates Gi, locking it OFF ("disables the inhibitor") → also ↑ cAMP → whooping cough.
Next best step: aggressive oral rehydration therapy — glucose-driven Na⁺ co-transport (SGLT1) stays intact, so oral fluids work; rehydration, not antibiotics, is the priority (doxycycline only shortens duration/shedding).
Vignette: A young girl has precocious puberty, large irregular café-au-lait macules ("coast of Maine" borders), and a fibrous dysplasia bone lesion that fractured.
Dx: McCune-Albright syndrome — postzygotic mosaic activating GNAS mutation.
Mechanism: constitutive Gsα activation → chronic ↑ cAMP → autonomous hormone hypersecretion (precocious puberty; sometimes acromegaly, hyperthyroidism, Cushing). The mutation is lethal if germline, so it survives only as mosaicism — explaining the patchy, segmental presentation.
Contrast: loss-of-function Gsα (pseudohypoparathyroidism 1A / Albright hereditary osteodystrophy) causes PTH resistance → ↓Ca²⁺, ↑PO₄³⁻, ↑PTH, short 4th/5th metacarpals.
cAMP (Gs) hormones — "FLAT ChAMP": FSH, LH, ACTH, TSH, CRH, hCG, ADH (V2), MSH, PTH (also glucagon, calcitonin, GHRH).
IP₃/Gq hormones — "GOAT HAG": GnRH, Oxytocin, ADH (V1), TRH, Histamine (H1), Angiotensin II, Gastrin.
JAK-STAT ligands — "PIGGLET": Prolactin, Immunomodulators (IL-2/-6, IFN), GH, G-CSF, Leptin, EPO, TPO.
Gi receptors — the "MAD 2s": M2, Alpha-2, D2.
Toxins: Cholera → Gs Stays on; Pertussis → Gi Poops out (off) — both raise cAMP. (Note ADH appears twice: V2→Gs/cAMP in kidney, V1→Gq/IP₃ in vascular smooth muscle.)
Receptor superfamilies at a glance
| Receptor family | Signal / 2nd messenger | Speed | Example ligands |
|---|---|---|---|
| GPCR | cAMP or IP₃/DAG/Ca²⁺ | seconds | epinephrine, glucagon, ACh |
| Receptor tyrosine kinase | RAS/MAPK, PI3K/Akt | minutes | insulin, IGF-1, EGF, FGF, PDGF |
| JAK-STAT | STAT → transcription | min–hrs | GH, prolactin, EPO, cytokines |
| Guanylyl cyclase | ↑ cGMP → PKG | seconds | NO, ANP, BNP |
| Nuclear/intracellular | direct gene transcription | hrs–days | steroids, T3/T4, vitamin D |
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