Cell Signaling

Receptors and Signal Types

• Signaling spans endocrine (blood-borne, slow), paracrine, autocrine, juxtacrine, and synaptic modes.
• Four receptor families: G-protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), ligand-gated ion channels, and intracellular receptors for lipid-soluble ligands. Steroid and thyroid hormones cross the membrane and act directly as transcription factors — slow but long-lasting.

GPCRs and Second Messengers

• Ligand binding makes $G\alpha$ swap GDP for GTP: $G_s$ activates adenylyl cyclase (cAMP up, PKA on), $G_i$ inhibits it, $G_q$ activates phospholipase C to make $IP_3$ (releases ER $Ca^{2+}$) and DAG (activates PKC).
• Cholera toxin locks $G_s$ on and pertussis toxin locks $G_i$ off — both raise cAMP. Caffeine and sildenafil inhibit phosphodiesterases, prolonging cAMP or cGMP signals.

RTKs, Amplification, and NO

• RTKs dimerize and autophosphorylate tyrosines, recruiting adapters into the Ras-MAPK growth cascade; constitutively active RTKs (HER2, EGFR) and GTPase-dead Ras drive cancer.
• Each cascade step multiplies the signal: $1 \text{ ligand} \to \text{many G-proteins} \to \text{many cAMP} \to \text{millions of products}$
• Nitric oxide diffuses through membranes, activates guanylyl cyclase, raises cGMP, and relaxes smooth muscle.

Key Takeaways

• Know what each $G\alpha$ subtype does and which second messengers result.
• RTKs signal growth via dimerization and Ras-MAPK — no G-proteins involved.
• Amplification explains why hormones act at nanomolar concentrations.
• Desensitization (arrestin, internalization, downregulation) explains drug tolerance.