Week 4

• Adrenergic Receptor


  Receptor that binds to adrenergic neurotransmitters like noradrenaline

  
• Receptor


  Binding site for a ligand
• Receptor Subtype


  Different versions of the same receptor
• Signalling


  The process by which a receptor transduces an extracellular signal into an intracellular response
• Adrenergic receptors


  • OFF - Receptor bound to G protein
  • ON - Receptor and G-protein dissociate
• Smooth muscle cells


  Muscle cells that line the inside of blood vessels and other organs
• Adrenergic receptor subtypes


  • Alpha 1
  • Beta 2

  
• Alpha 1 receptor


  Causes contraction of smooth muscle

  
• Beta 2 receptor


  Causes relaxation of smooth muscle

  
• Both Alpha 1 and Beta 2 receptors respond to noradrenaline
• Adrenergic receptor agonists

  
• Beta 1 Adrenoceptor


  Found in lung smooth muscle cells

  
• Beta 2 Adrenoceptor


  Stimulates bronchodilation

  
• Noradrenaline binding


  1. Stimulates adenylate cyclase

  2. Increases cAMP levels

  3. Activates protein kinase A (PKA)

  4. Inactivates myosin light chain kinase

  
• Adrenergic Synapse


  • 3 components:
  • The noradrenergic synapse
  • Adrenoceptors
  • Noradrenergic synapse pharmacology

  
• The noradrenergic synapse


  • Fight or flight system
  • Rest and digest system
  • Two branches of autonomic system
• Sympathetic nervous system


  Fight or flight
• Noradrenaline


  • Main neurotransmitter of sympathetic nervous system
  • Fight or flight

  
• Noradrenaline regulation


  1. Termination of signal

  2. Noradrenaline synthesis

  3. Noradrenaline uptake into storage vesicles

  4. Noradrenaline release

  5. Regulation of noradrenaline release

  
• vMAT


  Vesicular monoamine transporter

  
• Ca2+-mediated exocytosis


  Noradrenaline release

  
• Termination of signal


  1. Noradrenaline uptake

  2. Noradrenaline metabolism

  
• Uptake 1


  • Noradrenaline transporter
  • 75% repackaged into vesicles by vMAT

  
• Uptake 2


  • Remaining 25% uptaken by nearby non-neuronal cells
  • Extraneuronal monoamine transporter (EMT)

  
• Noradrenaline metabolism


  • Noradrenaline is metabolised by two intracellular enzymes – monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)
  • MAO is bound to the surface membrane of mitochondria

  
• Adrenoceptors


  G protein coupled receptors
• The GTPase cycle


  1. GDP-bound (G protein OFF)

  2. GTP-bound (G protein ON)

  3. GTPase Activating Protein

  4. Guanine exchange factor
• Adrenergic receptors


  • G protein coupled receptors
  • OFF – Receptor bound to G protein
  • ON – Receptor and G-protein dissociate
• Adrenoceptor Subtypes


  • α1
  • α2
  • β1
  • β2
  • β3
• α1 adrenergic receptor signalling

  1. Gq protein

  2. Noradrenaline binging leads to activation of phospholipase C (PLC)

  3. Catalyses: Phosphatidylinositol 4,5-bisphosphate PIP2 breakdown to diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3)

  4. IP3 opens calcium channels on the sarcoplasmic reticulum/endoplasmic reticulum

  5. Increases cytoplasmic calcium concentrations

  6. Increased calcium stimulates contraction

  
• Physiological Consequence of α1 adrenoceptor activation

  • Smooth muscle contraction
  • Stimulates vasoconstriction
  • Increases blood pressure

  
• α2 adrenoceptor signalling


  1. Noradrenaline binding release the inhibitory Gi protein

  2. Inactivates adenylate cyclase (AC)

  3. Deceases cAMP levels and inactivates protein kinase A (PKA)

  4. Inactivates voltage gated calcium channels

  
• β1 Adrenoceptor signalling


  1. Noradrenaline binding activates adenylate cyclase (AC)

  2. Increases cAMP levels and activates protein kinase A (PKA)

  3. Opens plasma membrane and sarcoplasmic reticulum calcium channels

  4. Increases cytoplasmic calcium concentration

  
• Physiological Consequence of β1 Adrenoceptor activation

  Stimulates cardiac contraction

  
• β2 Adrenoceptor signalling


  1. Noradrenaline binding stimulates adenylate cyclase

  2. Increases cAMP levels and activates protein kinase A (PKA)

  3. Inactivate myosin light chain kinase

  
• Physiological Consequence of β2 Adrenoceptor activation

  Stimulates bronchodilation

  
• β3 Adrenoceptor signalling


  1. Noradrenaline binding stimulates adenylate cyclase

  2. Increases cAMP levels activating protein kinase A (PKA)

  3. Stimulates breakdown of lipid

  
• Physiological Consequence of β3 Adrenoceptor activation

  Regulates lipolysis
• Adrenergic Receptors


  Receptors activated by noradrenaline

  
• Noradrenaline regulation


  1. Synthesis

  2. Storage

  3. Release

  4. Uptake

  5. Metabolism