Muscarinic Receptors

How do Muscarinic receptors work?

• M2 receptors are activated by acetylcholine release from vagal stimulation
  • The activated M2 receptor activates a G protein (Gi), which binds to adenylate cyclase and inhibits its activation. This results in less cAMP being produced and thus less Ca influx into the cell at the time of the next action potential.
  • The activated Gi protein activates a K channel (K_ACH) that promotes the loss of K and causes resting membrane potential to become more negative (hyperpolarize) at the end of Phase 3 of the action potential of the SA node thus slowing the heart rate (Phase 4 takes longer to reach threshold and fire).
  • In addition to inhibiting adenylate cyclase, M2 activation may activate a guanylate cyclase enzyme system to increase the level of cGMP in the cell, which reduces the flow of Ca across the L type Ca channel during Phase 2 of the action potential thus mediating a reduction in contractility.
  • M2 receptors are also located on the pre-synaptic nerve terminal and function to inhibit the release of norepinephrine from the nerve terminal thus reducing the activity of the sympathetic system.

• M3 receptor activation is unclear.
  • Acetylcholine probably activates this receptor.
  • It appears to result in the activation of nitric oxide within the membrane resulting in the activation of adenylate-guanylate cyclase and increase in cGMP within the vascular smooth muscle cell.
  • Cyclic GMP inhibits the myosin light chain kinase, which is responsible for activation of the myosin head and cross bridge formation.

• Cyclic GMP may also inhibit Ca entry into the smooth muscle cell thus promoting vasodilation