Beta Receptors

How do Beta receptors work?

• Activation of a beta receptor by epinephrine or norepinephrine results in activation of the cytosolic messenger cAMP which promotes the opening of the Ca channel during the action potential
• The activated beta receptor (a transmembrane protein) induces a series of changes to the membrane bound G protein complex (G proteins are classified as stimulatory (Gs) or inhibitory (Gi); in the case of beta receptor activation a Gs is involved).
• The activated Gs protein itself activates the transmembrane enzyme system called adenyl cyclase (also called adenylate cyclase).
• The triple combination of beta receptor, G protein complex, and adenyl cyclase is termed the beta-adrenergic system.
• Activation of adenylate cyclase produces intracellular cAMP from ATP.
  • Cyclic AMP is the second messenger of the beta-adrenergic system.
• Cyclic AMP induces the activation of a number of third intracellular messengers called protein kinases, specifically protein kinase A (PKA).
• Protein kinases phosphorylate various important proteins and enzymes.
  • PKA phosphorylates the Ca channel protein (L type) enhancing Ca entry into the cell during Phase 2 of the action potential. This starts the process of Ca induced Ca release and contraction.
  • PKA also phosphorylates phospholamban, releasing the inhibition of SERCA, resulting in Ca uptake by the SR and induction/promotion of diastole and relaxation.
• Phosphodiesterases within the cytosol are responsible for the degradation of cAMP promoting the “turning off” of beta stimulation.
• Beta2 receptors on the vascular smooth muscle wall are activated mainly by epinephrine
  • As with Beta receptors on the heart, Beta2 vascular receptors result in the release of cytosolic cAMP.
  • Cyclic AMP inhibits the myosin light chain kinase, a protein that enables actin-myosin interaction, hence Beta 2 stimulation promotes vasodilation.
• PKA, activated by cAMP, is responsible for phosphorylating several proteins involved in contraction and relaxation:
  • Phosphorylates the L type Ca channels causing an increase in Ca flux into the cell during phase 2 of the action potential.
  • Phosphorylates the ryanodine receptor causing an increase in Ca released from the SR.
  • Phosphorylates phospholamban releasing its inhibition of the activity of SERCA causing an increase in Ca uptake in the SR.
  • Phosphorylates Tn-I thereby decreasing the sensitivity of Tn-C for Ca thus enhancing relaxation.