Receptors

• Receptor Types
  • Intracellular receptors
    • Examples of ligands: Glucocorticoids
  • Cell surface receptors
    • G protein-coupled receptors
      • Examples of ligands: Catecholamines
    • Receptor tyrosine kinases
      • Examples of ligands: Insulin
    • Receptors with associated kinases
      • Examples of ligands: Growth hormones
    • Receptor protein serine/threonine kinases
      • Examples of ligands: TGF-β (cytokine)
    • Ligand-gated ion channels
      • Examples of ligands: Acetylcholine

Receptor tyrosine kinases (RTKs)

• Examples of ligands: insulin, growth factors (e.g., EGF, IGF, FGF, TGF)
  • Activation of tyrosine kinase → ↓ cAMP → activation of protein phosphatase 1 (PP 1) → PP 1-mediated dephosphorylation deactivates glycogen phosphorylase and activates glycogen synthase → ↓ glycogenolysis and ↑ glycogen synthesis

Non-receptor tyrosine kinases

• Examples of ligands: growth hormone, prolactin, erythropoietin, thrombopoietin, cytokines (e.g., G-CSF, IFN, IL-2, IL-6)
• Activation principle (similar to receptor tyrosine kinases)
  1. Ligand binding leads to receptor dimerization.
  2. Two neighboring tyrosine kinase domains of JAK phosphorylate each other (autophosphorylation) → JAK activation
  3. Development (at the phosphorylated tyrosine residues) of binding sites for SH2 domains of signal proteins (STAT proteins).
  4. STAT proteins are phosphorylated and dimerized by JAK.
  5. STAT dimers exert their effect directly in the nucleus as a transcription factor for JAK-STAT regulated genes.

Ligand-gated ion channels

• Since most ligands of ligand-gated ion channels are neurotransmitters, only a short overview is provided here.
  • Examples of ligands: acetylcholine, GABA_A, glutamate, IP3
  • Receptors: Nicotinic Acetylcholine Receptors (nAChRs), GABA/Glycine Receptors, Glutamate Receptors
  • Receptor structure: Cell surface receptors that act as ion channels
  • Activation principle (example)
    1. Ligand binding → conformational change
    2. Pore opening enables ion movement (Na+, K+ Ca²⁺, Cl-) across the cell membrane.
    3. Altered membrane potential → rapid signal response

Second messengers

cAMP (cyclic adenosine monophosphate) and protein kinase A

• Regulation of adenylyl cyclase: depends on the type of G protein of the G protein-coupled receptor
  • Gs proteins: activate adenylyl cyclase → ↑ cAMP
  • Gi proteins: inhibit adenylyl cyclase → ↓ cAMP
• Effects
  • cAMP activates protein kinase A (PKA).
  • Mechanism: PKA controls the activity (activation or inactivation) of numerous enzymes via phosphorylation of serine and threonine residues.
  • Example: glycogen metabolism to ↑ blood glucose concentration
    • Hypoglycemia → ↑ glucagon or adrenaline → GPCR activation → ↑ cAMP → activation of PKA, which causes:
      • Phosphorylation of glycogen phosphorylase → activation → increased mobilization of glucose from glycogen
      • Phosphorylation of glycogen synthase → inhibition→ decreased glycogen formation
• Degradation
  • cAMP is degraded by phosphodiesterase to adenosine monophosphate (AMP).
• Examples of ligand hormones
  • Hypothalamic hormones: GHRH, CRH, vasopressin (V2 receptor)
  • Pituitary hormones: TSH, ACTH, FSH, LH, MSH
  • Other hormones: PTH, calcitonin, glucagon, histamine (H2 receptor), hCG

cGMP (cyclic guanosine monophosphate)

• Synthesis: cGMP is synthesized from GTP by the guanylate cyclase. There are two subforms of guanylate cyclase:
  • Soluble guanylate cyclase: activated by nitric oxide
  • Membrane-bound guanylate cyclase: activated through extracellular ligand binding (e.g., EDRF, ANP, BNP)

• Effects
  • Activates cGMP-dependent protein kinase G in smooth muscle cells → inhibits Ca²⁺ outflow from the sarcoplasmic reticulum → ↓ intracellular Ca²⁺ → relaxed smooth vascular muscles → vasodilation
  • cGMP-dependent ion channels in the photoreceptor cells of the retina → preserve the unstimulated state → dark signal
• Degradation: by phosphodiesterase to GMP
  • So PDE inhibitors work as vasodilators, used in the treatment of pulmonary hypertension (PDE-4 inhibitor roflumilast) and erectile dysfunction (PDE-5 inhibitor sildenafil).

IP3 and DAG

• Synthesis
  1. Activation of a Gq protein-coupled receptor
  2. Activation of phospholipase C (an enzyme that cleaves phospholipids)
  3. Cleaving of the membrane-bound phospholipids PIP2 (phosphatidylinositol 4,5-bisphosphate) into the second messenger IP3 (inositol triphosphate) and DAG (diacylglycerol)
• Function
  • IP3 (hydrophilic) diffuses into the cytoplasm → activation of IP3 receptors at the membrane of the endoplasmic reticulum (ER) → Ca²⁺ release from the ER via the IP3 receptor-coupled calcium channel → ↑ intracellular Ca²⁺ concentration → smooth muscle contraction
  • DAG (lipophilic) remains in the membrane → activates protein kinase C (PKC)
  • PKC is Ca²⁺-dependent (depends on IP3-mediated Ca²⁺ release)
• Mechanism of action: regulates the activity of various enzymes via phosphorylation of serine and threonine residues, e.g., regulatory proteins that influence cell growth (actin cytoskeleton) or differentiation (EGFR)
• Examples of the effect of PKC: cell growth and proliferation
• Examples of ligands: vasopressin (V1 receptor), oxytocin, GnRH, TRH, angiotensin, gastrin, histamine (H1 receptor)

Ca²⁺ as a second messengers

• Effect of Ca²⁺, especially as a complex with calmodulin: One molecule of calmodulin binds up to four Ca²⁺ ions → conformational change → regulation of calmodulin-dependent kinases/phosphatases, e.g., CaM kinase III (protein synthesis)