Lecture 9

• Hormone


  Binds to receptor
• Receptor


  • Changes conformation and activity
  • Alters activity of intracellular signaling pathways
  • Leads to change in synthesis of target proteins and/or modification of existing target proteins

  
• Receptors


  • Large proteins
  • Families
  • Can be multiple receptors for one ligand or more than one ligand for a receptor
  • Variable number in target cell (~500-100,000)
  • Can be activated and inhibited
  • Located in cell membrane, cytoplasm, nucleus

  
• Receptor properties


  • High affinity
  • Saturable
  • Specific
  • Reversible
• Hormone A binds to receptor B which causes response C. The concentration of hormone A doubles in the body causing a doubling in response C. The concentration of hormone A doubles again, but this time no change in response C.

  
• Receptor B is saturated


  No change in response C when hormone A concentration doubles again
• Hormone signaling


  1. Hormone binds to receptor

  2. Changes the conformation and activity of the receptor

  3. Alters the activity of intracellular signaling pathways

  4. Leads to change in synthesis of target proteins (slow) and/or modification of existing target proteins(fast)

  
• Types of receptors

  • Intracellular receptors (bind lipid soluble hormones)
  • Plasma membrane receptors

  
• Intracellular receptors


  • Cytosolic and nuclear
  • Directly alter gene transcription = genomic effects
• Plasma membrane receptors


  • G protein-coupled receptors
  • Receptor-enzyme receptors
  • Receptor-Channel
  • Integrin Receptor

  
• Peptide hormones


  • Cannot penetrate target cell
  • Bind to surface receptors and activate intracellular processes through second messengers

  
• Steroid hormones


  • Penetrate plasma membrane and bind to internal receptors (usually in nucleus)
  • Influence expression of genes of target cell
  • Take several hours to days to show effect due to lag for protein synthesis
• Hormone response elements


  • Specific DNA sequences
  • Only genes with the response elements will be activated/repressed

  
• G Protein–Coupled Receptors (GPCR)


  • Membrane-spanning proteins
  • Cytoplasmic tail linked to G protein, a three-part transducer molecule
  • G protein-coupled adenylyl cyclase-cAMP system is the signal transduction system for many protein hormones
  • G protein-coupled receptors use some lipid second messengers: e.g., diacylglycerol (DAG) and inositol trisphosphate (IP3)
  • When G proteins are activated, they open ion channels in the membrane and alter enzyme activity on the cytoplasmic side of the membrane

  
• GPCR-Adenylyl Cyclase Signal Transduction and Amplification


  1. Signal molecule binds to G protein–coupled receptor (GPCR), which activates the G protein

  2. G protein turns on adenylyl cyclase, an amplifier enzyme

  3. Adenylyl cyclase converts ATP to cyclic AMP

  4. cAMP activates protein kinase A

  5. Protein kinase A phosphorylates other proteins, leading ultimately to a cellular response

  
• 3 main types of G proteins

  • Gs (Adenylyl cyclase stimulatory)
  • Gq (Phospholipase C stimulatory)
  • Gi (Adenylyl cyclase inhibitory)

  
• Fight or flight responses mediated by G-protein coupled receptors

  • Liver: glucose release
  • Fat: fatty acid release
  • Heart: muscle contraction
  • Skeletal muscle blood vessels: less vasoconstriction
  • Intestine, skin, kidney: vasoconstriction
• Epinephrine can bind to different isoforms of the adrenergic receptor
• 1. Receptor


  Intestinal blood vessel constricts
• b2-Receptor


  Skeletal muscle blood vessel dilates
• Epinephrine, norepinephrine signaling


  1. Adrenergic Receptor

  2. G proteins

  3. Adenylyl Cyclase

  4. cAMP

  5. Protein kinase A

  6. Protein phosphorylation

  7. Phospholipase C

  8. Inositol triphosphate

  9. Diacylglycerol

  10. Protein kinase C

  11. Ca2+
• The alpha subunit has multiple isoforms: Gas, Gai, Gaq responsible for signaling
• Gas


  Adenylyl cyclase cAMP PKA cell response
• Gai


  (-) adenylyl cyclase cAMP
• Gaq


  (a) DAG PKC (b) IP3 Ca2+ Cellular response
• How signalling is modulated

  • Hormone degraded
  • Receptor down-regulation or up-regulation
  • Receptor desensitization
  • Breakdown of second messengers
  • Modification of any component in the pathway
  • Biological effect provides feedback to reduce hormone secretion

  
• Membrane receptors


  • 2 Zn fingers on either side of hormone binding domain
• Key points of lecture

  • Receptors – two types (intracellular and membrane bound – how they work)
  • Intracellular primarily work through gene transcription and translation (and some cell signaling)
  • Membrane bound can alter membrane potential, work through cell signaling, influence transcription, translation, metabolism etc.
  • Epinephrine can cause diverse physiological effects through different receptors