Membrane Receptors and Signal Transduction

Receptor Basics - Lock & Key Chat

• Receptor: Cellular protein binding specific ligands (hormones, neurotransmitters, drugs).
• Binding Models:
  • Lock & Key: Rigid, complementary shapes.
  • Induced Fit: Ligand binding alters receptor shape (more accurate).
• Key Properties:
  • Affinity: Binding strength. ↓$K_d$ (dissociation constant) = ↑affinity.
  • Specificity: Distinguishing between ligands.
  • Efficacy: Ability to activate receptor & elicit response.
• Ligand Actions:
  • Agonist: Activates receptor (affinity + efficacy).
    • Full: Max effect.
    • Partial: Submaximal effect.
  • Antagonist: Blocks receptor (affinity, no efficacy).
  • Inverse Agonist: Produces effect opposite to agonist.

⭐ Many therapeutic drugs function by targeting receptors as agonists or antagonists.

GPCR Signaling - G-Protein Gala

GPCRs: Largest family, 7-TM helices. Mediate diverse signal responses.

• Mechanism:

  • Ligand binding → GPCR conformational change.
  • GPCR activates heterotrimeric G-protein (α, β, γ).
  • Gα exchanges GDP for GTP → Dissociates from Gβγ.
  • Gα-GTP & Gβγ modulate effectors.
  • Termination: Gα GTPase activity (GTP→GDP); reassociation.

• Major G-Protein Families & Effectors:

  • Gs (Stimulatory): Activates Adenylyl Cyclase (AC) → ↑cAMP → PKA. 📌 Stimulates Adenylyl Cyclase.
  • Gi (Inhibitory): Inhibits AC → ↓cAMP. 📌 Inhibits Adenylyl Cyclase.
  • Gq/11: Activates Phospholipase C (PLC) → PIP2 to IP3 & DAG. IP3 → ↑$Ca^{2+}$; DAG → PKC. 📌 Quts PIP2.

⭐ Cholera toxin ADP-ribosylates Gsα (active) → ↑cAMP → diarrhea. Pertussis toxin ADP-ribosylates Giα (inactive) → ↑cAMP → whooping cough.

RTKs & Ion Channels - Kinase Kickstart & Ion Influx

• Receptor Tyrosine Kinases (RTKs)
  • Mechanism: Ligand binding → Dimerization of receptors → Autophosphorylation of tyrosine residues → Recruits SH2-domain proteins (e.g., Grb2) → Activates downstream MAPK, PI3K-Akt pathways.
  • Key Examples: Insulin R, EGF R, PDGF R.
  • Functions: Regulates crucial cell processes: growth, proliferation, differentiation, survival, metabolism.
  • 📌 Mnemonic: Receptors That Kinase (phosphorylate) Tyrosine.
• Ligand-gated Ion Channels (Ionotropic Receptors)
  • Mechanism: Ligand binds to receptor → Conformational change → Channel pore opens → Specific ion flux ($Na^+$, $K^+$, $Ca^{2+}$, $Cl^-$) → Rapid change in membrane potential → Fast cellular response (e.g., neurotransmission).
  • Key Examples: Nicotinic AChR, GABA-A R, NMDA R.
  • Functions: Key for rapid neurotransmission, muscle cell excitation, sensory transduction.

⭐ Insulin receptor (RTK): intrinsic tyrosine kinase activity. Activation recruits IRS, promotes GLUT4 translocation for glucose uptake.

Signal Pathways & Clinical - Pathway Powwow & Rx Relevance

• Key Second Messengers:
  • $Ca^{2+}$/Calmodulin: Muscle contraction, secretion.
  • $IP_3$/DAG: From $PIP_2$ (PLC). $IP_3 \rightarrow Ca^{2+}$ release; DAG $\rightarrow$ PKC activation.
  • Nitric Oxide (NO): Activates guanylyl cyclase $\rightarrow$ ↑cGMP (vasodilation).
• Signal Amplification: Cascades (e.g., one receptor $\rightarrow$ many G-proteins).
• Signal Termination:
  • Ligand dissociation.
  • Gα GTP hydrolysis.
  • Phosphodiesterases (PDEs) degrade cAMP/cGMP.
  • Receptor downregulation.
• Clinical/Rx Examples:
  • β-blockers: GPCR antagonists (hypertension).
  • Sildenafil: PDE5 inhibitor $\rightarrow$ ↑cGMP (erectile dysfunction).
  • Lithium: Modulates $IP_3$ pathway (bipolar disorder).

  ⭐ Cholera toxin: ADP-ribosylates Gαs $\rightarrow$ persistent ↑cAMP $\rightarrow$ severe diarrhea.

  • Pertussis toxin: ADP-ribosylates Gαi $\rightarrow$ ↑cAMP (whooping cough). 📌 Gs 's'timulatory ON (Cholera), Gi 'i'nhibitory OFF (Pertussis) $\rightarrow$ both ↑cAMP.

High‑Yield Points - ⚡ Biggest Takeaways

• GPCRs, largest family, use heterotrimeric G-proteins: Gαs → ↑cAMP (PKA); Gαq → IP3/DAG (PKC).
• Adenylyl cyclase forms cAMP; phosphodiesterases degrade it.
• Phospholipase C produces IP3 (↑Ca²⁺) & DAG (PKC activation).
• Receptor Tyrosine Kinases (RTKs) (e.g., insulin receptor) autophosphorylate, activating MAPK or PI3K/Akt pathways.
• JAK-STAT pathway for cytokine receptors involves Janus Kinases (JAKs) and STATs.
• Key second messengers: cAMP, cGMP, Ca²⁺, IP3, DAG.