(A) The binding of norepinephrine to the orthosteric site of the βAR leads to the formation of a high-affinity ternary complex composed of agonist, βAR, and heterotrimeric G protein (including Gα, Gβ, and Gγ). Competitive radioligand-binding assays show shifted curves in the presence of G protein (Gs). A leftward curve shift indicates allosteric cooperativity and stabilization of a high-affinity receptor conformation. The high-affinity ternary complex stimulates G protein–mediated cAMP accumulation and intracellular signaling. As a physiological consequence, heart rate and contractility increase. β-Arrestins are recruited to agonist-occupied GPCR kinase (GRK) phosphorylated receptors to turn off, or desensitize, the G protein signal by sterically preventing G protein binding. β-Arrestin also stabilizes a high-affinity conformation of the βAR, as reflected by the leftward shift in the competition radioligand binding curve. β-Arrestin mediates receptor endocytosis and functions as a scaffold for many signaling proteins, thereby activating a suite of distinct β-arrestin–dependent signaling pathways. β-Arrestin–mediated signaling can occur inside the cell, initiated by the internalized receptor–β-arrestin complex, or at the plasma membrane via EGFR transactivation and ERK activation. Notably, the transactivation pathway is cardioprotective. (B) Biased signaling is a process whereby alternate GPCR ligands preferentially stimulate cellular pathways through differential engagement of a transducer, either G proteins or β arrestins, leading to distinct signaling profiles.