Second Messengers

Second Messengers

1. Cyclic AMP

   • Features
     • In low concentrations in resting cells (good because you dont want any activator to be present
     • Produced rapidly by adenylate cyclase in response to agonist (which allows the second messenger to act quickly)
     • After it is produced it then binds to regulatory subunits of protein kinase A (PKA). The PKA would usually be bound to catalytic subunits. Once cAMP binds to the the PKA goes off and phosphorylates other things.
     • cAMP is destroyed by phosphodiesterase when no longer needed. This stops the agonist from having its desired effect, prevents permanent activation
   • Manipulation
     • Forskolin
       • A drug called forskolin can activate the adenylate cyclase to produce cAMP from ATP and skip the activation of the GPCR and then the Alpha S subunit
       • Forskolin is an experimental drug
     • Dibutyryl cAMP
       • The cAMP then attaches to the two regulatory subunits activating the catalytic subunits
       • cAMP can be mimicked experimentally by dibutyryl cAMP which is lipid soluble and can enter cells
     • H89
       • Binds directly to catalytic subunits and stops them from working
     • Phosphodiesterase inhibitor
       • These can increase the amount of cAMP present by preventing cAMP breakdown. These include: isobutyl methyle xanthine, papaverine (used to prevent muscle contraction) , caffeine
   • Actions of cAMP
     • uncoupling of g proteins from receptors limits cAMP produced when at high conc. of cAMP

2. Glycogen Metabolism

   • Glycogen is metabolised to glucose-1-phosphate using cAMP
   • The cAMP activates the catalytic subunits. these then phosphorylate phosphorylase kinase making it active. The active form of phosphorylase kinase then phosphorylates glycogen phosphorylase also making it active. Finally the glycogen phosphorylase converts glycogen to glucose-1-phosphate
   • This process involved amplification which uses a small amount of cAMP which inturn phosphylates increasingly more molecules in each stage of the process. Therefore small amount of cAMP makes a larger change

3. Phosphoinositides

   • Membrane phosphates based on insitol, which when metabolised yield many second messenger molecules.

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