Receptors Types and Mechanisms

Metabotropic Receptors (GPCRs)

  • Metabotropic receptors are also known as G protein-coupled receptors (GPCRs).
    • GPCRs are sometimes called "magnificent seven" due to their seven transmembrane domains.
    • They form a large and closely related family of proteins.
    • Ligands typically bind to the extracellular domain of the receptor.
    • Upon activation, GPCRs can activate ion channels or enzymes.

GPCR Activation of Ion Channels

  • Example: Muscarinic receptors.
    • Acetylcholine binds to the muscarinic receptor.
    • This activates a G protein.
    • The activated G protein then activates an ion channel.
    • In the heart, this process can open a potassium channel and slow the heart rate.

GPCR Activation of Enzymes

  • Adrenaline binds to its receptor.
    • This activates a G protein.
    • The activated G protein activates an enzyme.
    • The enzyme initiates a second messenger cascade, such as cyclic AMP (cAMP) production.
Typical Enzymes Involved in GPCR Signaling
  • Kinases: Enzymes that add a phosphate group (PO43−PO_4^{3-}).
  • Phosphodiesterases: Enzymes that remove a phosphate group.
  • Phospholipases: Enzymes that break down phospholipids in the membrane.
Examples of Specific Enzymes:
  • PKA (Protein Kinase A)
    • A protein kinase activated by cyclic AMP (cAMP).
    • Phosphorylates other proteins.
  • PKG (Protein Kinase G)
    • A protein kinase activated by cyclic GMP (cGMP).
    • Phosphorylates other proteins.
  • PKC (Protein Kinase C)
    • A protein kinase activated by calcium (Ca2+Ca^{2+}).
    • Phosphorylates other proteins.
  • Cyclases:
    • Enzymes that convert ATP or GTP into cyclic AMP (cAMP) or cyclic GMP (cGMP), respectively.
    • Guanylyl cyclase converts GTP to cGMP.
Phospholipase C Activation
  • G protein-coupled receptors can activate phospholipase C.
  • Phospholipase C breaks down PIP2 (phosphatidylinositol bisphosphate), a phospholipid in the cell membrane.
  • This breakdown produces two products:
    • Diacylglycerol (DAG): A lipid-soluble mediator that remains in the membrane and activates protein kinase C (PKC).
    • Inositol Trisphosphate (IP3): A soluble molecule that diffuses through the cell and mobilizes calcium (Ca2+Ca^{2+}) from intracellular stores.
    • The released calcium also contributes to PKC activation.
Phosphodiesterases (PDEs)
  • PDEs break down cyclic nucleotides like cAMP and cGMP.
    • Example: Caffeine inhibits PDEs, leading to increased cAMP levels.
    • Sildenafil (Viagra) inhibits a specific PDE that breaks down cGMP.

G Protein Cycle

  • G proteins consist of three subunits: alpha ($\alpha$), beta ($\beta$), and gamma ($\gamma$).
  • In the resting state, the alpha subunit is bound to GDP (guanidine diphosphate).
  • When an agonist binds to the GPCR, a conformational change occurs.
  • This change causes GDP to be replaced by GTP (guanidine triphosphate), activating the G protein.
  • The alpha subunit, now bound to GTP, and the beta-gamma subunits dissociate and can interact with downstream effectors (e.g., enzymes, ion channels).
  • The alpha subunit has GTPase activity.
    • It hydrolyzes GTP back to GDP, which inactivates the alpha subunit.
    • The alpha, beta, and gamma subunits then reassociate, returning the G protein to its resting state.

General Principle of Protein Activation and Inactivation

  • Proteins can be switched on or off through two primary mechanisms:
    • Nucleotide Binding: Activation often involves the binding of ATP or GTP.
    • Phosphorylation: Kinases add phosphate groups to activate proteins, while phosphatases remove phosphate groups to deactivate proteins.
      • Note: Phosphatases, not "diesterases," are the general term for enzymes removing phosphate groups.

GPCRs in Asthma: Beta-2 Adrenergic Receptors

  • Asthma involves bronchospasm (smooth muscle constriction in the airways), inflammation, and edema.
  • The sympathetic nervous system mediates bronchodilation through beta-2 adrenergic receptors.
  • Noradrenaline (norepinephrine) released by sympathetic nerves activates beta-2 receptors in the lungs.
  • This activates adenylyl cyclase, increasing cyclic AMP (cAMP) levels.
  • Cyclic AMP inhibits myosin light chain kinase in smooth muscle, leading to bronchodilation.

Structure-Activity Relationships (SAR) of Adrenergic Drugs

  • Adrenergic Receptors: Also known as catecholamine receptors
  • Types: Alpha ($\alpha$) and Beta ($\beta$) receptors
  • Alpha Receptors: Generally increase blood pressure and cause vasoconstriction and bronchoconstriction.
  • Beta Receptors:
    • Beta-1 ($\beta_1$): Primarily in the heart, increase heart rate.
    • Beta-2 ($\beta_2$): Primarily in the lungs, cause bronchodilation.
Development of Selective Beta-2 Agonists
  • Basic Catecholamine Structure: Has no activity on alpha or beta receptors.
  • Adding one -OH group has a little bit of an affect.
  • Adding a second -OH, you get some activity on both alpha and beta.
  • Adding a third -OH, you get full activity on alpha and beta.
  • Isoprenaline: A non-selective beta-agonist (affects both beta-1 and beta-2 receptors).
  • Salbutamol (Ventolin): A selective beta-2 agonist; revolutionized asthma treatment.
  • Terbutaline: A salbutamol "Me Too" drug; similar but slightly safer/more effective.

Enzyme-Linked Receptors

  • Less common as examples, but equally important.
    • Examples: insulin receptor, growth factor receptors.
  • Structure: Consist of subunits in the cell membrane
    • Ligand binding domain (extracellular)
    • Tyrosine kinase domain (intracellular)
  • Mechanism:
    • Ligand binding causes subunits to dimerize (come together).
    • Tyrosine kinase domains phosphorylate each other (autophosphorylation), activating the receptor.
    • Regulatory proteins bind to the activated receptor and trigger cellular responses.