1.The agonist binds to the myocardial beta1-adrenergic receptor. which is a typical G-protein coupled receptor.
2.In the unstimulated state the G-protein is complexed with GDP.
3. The receptor promotes exchange of GTP for GDP and release of G"/GTP.
4.The G"/GTP complex activates adenylate cyclase.
5.Intracellular cAMP increases and activates cAMP dependent protein kinase (PKA).
6.PKA phosphorylates the Ca2+ channel promoting Ca2+ influx.
7.Intracellular Ca2+ increases activating the contractile proteins.
8.PKA phosphorylates the sarcoplasmic reticulum leading to an increase in Ca2+ uptake and release.
9.PKA phosphorylates troponin changing its calcium binding kinetics
10.G" directly activates the Ca2+ channel.
11.Prolonged stimulation can lead to receptor down regulation via PKA and other protein kinases which phosphorylate the receptor. The other protein kinases which are involved in phosphorylation are referred to as G-protein coupled receptor kinases or GRKS. These phosphorylation steps lead to internalization of the receptor.
