Beyond G-protein-coupled receptor blockade.

Adrenergic β1 receptors signal through G-proteins (subunits αβγ) to activate adenylate cyclase 6. Desensitization of the receptors occurs through phosphorylation of its C-terminal loop by GRK2, which mediates binding of arrestins. Novel interventions include design of a biased agonist that specifically targets one second messenger over another, inhibition of GRK2 or inhibition of the arrestin–β receptor interaction, to prevent desensitization or activation of adenylate cyclase 6 to increase contractility.