03. Metabotropic Signalling

• GPCRs have slow response and indirect effects on channels and receptors
• Gi and Gs modulate cAMP signals

  • Gi reduces cAMP
  • Gs increases cAMP
• Gq GPCRs activate phospholipase C

  • hydrolysis of PIP2
  • production of IP3
  • IP3 acts on ER receptors -> release of Ca2+
  • causes activation of enzyme pathways that are calcium dependent
  • lead to phosphorylation of target channels or receptors
• GPCRs can be:

  • direct = no enzymes involved, just direct action of G proteins. beta gamma subunit interacts with the target
  • indirect = acts via second messenger like cAMP or IP3
• sites of action of GPCRs in neurones:

  • presynaptic = regulate NT release
  • postsynaptic = regulate excitability of the membrane
  • cell body = influence action potential
• indirect post-synaptic modulation:

  • slow EPSP generated
  • Gq coupled - activate phospholipase C
  • PIP2 keeps M-type K+ channel open
  • PIP2 hydrolysis due to GPCR activation -> M channel closes and reduced K+ efflux
  • slow depolarisation
• direct postsynaptic modulation:

  • e.g. mAChRs in cardiac muscle
  • decreases excitability
  • K+ channel opens (GIRK channel)
  • GPCR beta gamma subunit binds directly to GIRK opening it
  • K+ efflux and hyperpolarisation
• direct presynaptic modulation:

  • e.g. adrenergic post-ganglionic sympathetic neurones
  • adrenoceptor inhibits Ca2+ channels via beta gamma subunits
  • negative feedback - decreased Ca2+ entry leads to decrease NA release
• indirect presynaptic modulation:

  • e.g. serotonin
  • facilitates NT release
  • cAMP as second messenger causes closure of K+ channels
  • slower repolarisation and prolonged AP
  • increase Ca2+ entry
  • increased vesicle release