G-Protein Coupled Receptors (GPCRs)

GPCRs are 7-transmembrane domain receptors. The G-protein itself is a heterotrimeric (α, β, γ) intracellular protein. Ligand binding causes a conformational change, leading to the exchange of GDP for GTP on the α-subunit, which then dissociates and activates downstream effectors.

1. Gs and Gi (cAMP Pathway)

• Mechanism (Gs - stimulatory):
  1. Ligand binds GPCR → Gsα activated.
  2. Gsα activates Adenylyl Cyclase.
  3. Adenylyl Cyclase converts ATP → cAMP (second messenger).
  4. cAMP activates Protein Kinase A (PKA) → phosphorylation of intracellular proteins → cellular effect.
• Mechanism (Gi - inhibitory):
  1. Ligand binds GPCR → Giα activated.
  2. Giα inhibits Adenylyl Cyclase → ↓ cAMP → ↓ PKA activity.
• High-Yield Ligands & Receptors:
  • Gs (↑ cAMP): β-adrenergic (β1, β2), Glucagon, Histamine (H2), TSH, ACTH, FSH, LH, PTH, ADH (V2).
    • Mnemonic: "FLAT ChAMP" (FSH, LH, ACTH, TSH, CRH, hCG, ADH (V2), MSH, PTH, Calcitonin, GHRH, Glucagon).
  • Gi (↓ cAMP): α2-adrenergic, Muscarinic (M2), Dopamine (D2), Somatostatin.
• Key Associations:
  • Cholera Toxin: Irreversibly activates Gs → massive ↑ cAMP in intestinal mucosa → watery diarrhea.
  • Pertussis Toxin: Irreversibly inhibits Gi → massive ↑ cAMP → impairs phagocytosis.

2. Gq (IP3/DAG Pathway)

• Mechanism (Gq):
  1. Ligand binds GPCR → Gqα activated.
  2. Gqα activates Phospholipase C (PLC).
  3. PLC cleaves PIP2 → IP3 (inositol trisphosphate) and DAG (diacylglycerol).
  4. IP3 → binds to receptors on the ER → release of intracellular Ca²⁺.
  5. DAG and Ca²⁺ activate Protein Kinase C (PKC) → cellular effect (e.g., smooth muscle contraction).
• High-Yield Ligands & Receptors:
  • α1-adrenergic, Muscarinic (M1, M3), ADH (V1), Angiotensin II, Oxytocin, TRH, GnRH, Histamine (H1), Gastrin.
  • Mnemonic: "GOAT HAG" (GnRH, Oxytocin, ADH (V1), TRH, Histamine (H1), Angiotensin II, Gastrin).

3. cGMP Pathway

• Mechanism:
  • Nitric Oxide (NO): Diffuses into cell → activates soluble Guanylate Cyclase → GTP to cGMP.
  • ANP/BNP: Bind to receptor with intrinsic Guanylate Cyclase activity → GTP to cGMP.
  • cGMP activates Protein Kinase G (PKG) → smooth muscle relaxation (vasodilation).
• High-Yield Ligands:
  • Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP), Nitric Oxide (NO).
• Key Associations:
  • Sildenafil (Viagra): Inhibits cGMP phosphodiesterase (PDE-5), leading to ↑ cGMP and vasodilation.

4. Receptor Tyrosine Kinase (RTK) Pathway

• Mechanism:
  1. Ligand (often a growth factor) binding → receptor dimerization.
  2. Intrinsic tyrosine kinase domains autophosphorylate each other.
  3. Phosphorylated tyrosines serve as docking sites for signaling proteins (e.g., GRB2).
  4. Activates the RAS-MAP Kinase pathway → translocation to nucleus → influences gene transcription (cell growth, proliferation, differentiation).
• High-Yield Ligands:
  • Insulin, Insulin-like Growth Factor (IGF-1), Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor (PDGF), Fibroblast Growth Factor (FGF).
• Key Associations:
  • Mutations in RAS and other components of this pathway are common in many cancers (oncogenes).

5. Non-Receptor Tyrosine Kinase (JAK-STAT Pathway)

• Mechanism:
  1. Ligand (e.g., cytokine) binds to receptor → receptor dimerization.
  2. Receptor has no intrinsic kinase activity but recruits intracellular Janus Kinases (JAKs).
  3. JAKs cross-phosphorylate each other and the receptor.
  4. STATs (Signal Transducers and Activators of Transcription) dock on phosphorylated sites, are phosphorylated by JAKs.
  5. Phosphorylated STATs dimerize, translocate to nucleus, and act as transcription factors.
• High-Yield Ligands:
  • Cytokines (e.g., Interferons, Interleukins), Growth Hormone (GH), Prolactin, Erythropoietin (EPO), Thrombopoietin (TPO).
  • Mnemonic: "PIGGLET" (Prolactin, Immunomodulators, GH, G-CSF, EPO, TPO).
• Key Associations:
  • JAK inhibitors (e.g., Tofacitinib) are used to treat autoimmune conditions like rheumatoid arthritis.

6. Intracellular (Steroid) Receptor Pathway

• Mechanism:
  1. Lipophilic hormones (e.g., steroids, thyroid hormone) diffuse across the cell membrane.
  2. Bind to receptors in the cytoplasm or nucleus.
  3. Receptor-hormone complex undergoes a conformational change, translocates to the nucleus (if not already there).
  4. Binds to hormone-responsive elements (HREs) on DNA → acts as a transcription factor to regulate gene expression.
  5. Effects are slow (hours to days) but sustained.
• High-Yield Ligands:
  • Cytoplasmic receptors: Cortisol, Aldosterone, Testosterone.
  • Nuclear receptors: Thyroid hormone (T3/T4), Vitamin D, Estrogen, Progesterone.
  • Mnemonic for intracellular receptors: "VETTT CAP" (Vitamin D, Estrogen, Testosterone, T3/T4, Cortisol, Aldosterone, Progesterone).