G protein coupled receptors

G protein coupled receptors

1. Largest class of cell surface receptors

   • 700 human genes

2. Are associated with many diseases

   • Are therefore major therapeutic targets

3. Effects in cells are mediated by hetertrimeric g proteins

4. GPCRs

   • Ligands
     • Acetylcholine
     • Bradykinin
     • Dopamine
     • Epinephrine (adrenalin)
     • Glucagon
     • Histamine
     • Neurotensin
     • Prostoglandins
     • Serotonin
     • Thrombin
     • Vasopressin
     • Photons of light
   • Activation of Heterotrimeric G-Proteins
     • Binding of ligand allows receptor and g-protein to associate and triggers the exchange of GDP for GTP
       • The GTP bound G-protein is activated, causing release of the By complex
         • Both a and By are activated and both can play roles in signalling

5. G proteins and

   • cAMP
     • Some g-proteins regulate the production of cAMP
       • Cyclic AMP acts as a small intracellular mediator in all prokaryotic and animal cells
       • Classes
         • Gs
           • Stimulatory G protein
             • Activates adenlyl cyclase
         • Gi
           • Inhibitory G protein
             • Inhibits adenlyl cyclase
         • Pathogenic increase in cAMP
           • Cholera toxin
             • Transfers ADP ribose from NAD+ to Gs alpha subunit
               • Inhibits GTP hydrolysis
                 • Remains active
           • Pertussis toxin (Whooping cough)
             • Transfers ADP ribose to Gi alpha subunit preventing receptor interaction
               • Remains inactive
     • Normal concentration 10-7M
       • Extracellular signal can increase it >20 fold
     • Synthesised from ATP by plasma membrane bound adenylyl cyclase
       • Continually degraded by cAMP phosphodiesterase that hydrolyse the cAMP to adenosine 5'-monophosphate (5'AMP)
   • Inositol phosphates
     • Gq activates phospholipase C-beta
       • An important enzyme in lipid second messenger generation
   • Calcium
     • G proteins mediate ca2+ release through a number of mechanisms
       • Protein kinase C
         • Calcium dependent
   • Ion channels
     • Regulation by G proteins
       • Direct binding of By to ion channels
         • Muscarinic acetylcholine receptors
       • Indirectly through phosphorylation of ion channels by G protein regulated kinases
         • Such as PKA, PKC, Calmodulin-kinase
       • Indirectly through cyclic-nucleotide gating of ion-channels

6. Smell and sight

   • Signalling by Golf
     • cAMP binds to and opens a cAMP-gated Na+ channel, allowing influx of Na+
       • Depolarizes the olfactory receptor neuron and a nerve impulse travels along the axon to the brain
   • Response to light
     • A single photon of light converts 11-cis retinal to all-trans retinal causing a conformational change with activates the GPCR 'rhodopsin'
       • This causes dissociation of the Galpha subunit of heterotrimeric g protein transducin (Gt)
         • Gt activates a cyclic GMP phosphodiesterase, which hydrolyses cGMP to GMP
           • This closes cGMP-gated Na+ channels in the plasma membrane

7. Amplification

8. Desensitisation

   • Occurs on prolonged exposure to high concentrations of ligand
   • An adaptive and sometimes protective response
   • Reversible process
   • Types
     • Receptor inactivation
       • Uncoupling
       • Inactivated so that they no longer bind G proteins
     • Receptor sequestration
       • Temporarily internalised so they cant bind ligand
     • Receptor down-regulation
       • Destroyed in lysosomes after internalisation

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