Phosphorylation of β2-AR by GRK-2, -5, and -6 occurs in an agonist concentration-dependent manner to induce different receptor functions. High sympathetic firing activity (red lightning bolts) drives the β2-AR-Gs-independent (non-canonical) pathway by flooding the extracellular space with ligand (L, i.e. NE). Chronic receptor activation induces not only PKA-mediated phosphorylation of the receptor, but also phosphorylation by GRK5/6 (#1) instead of GRK2. Receptor phosphorylation by PKA and GRK5/6 promote receptor desensitization and internalization by recruiting β-arrestin 2 (β-ARR-2) to the receptor (#2). Once bound to the receptor, β-arrestin-2 acts as a scaffold for the sustained activation of the MAPK, ERK 1/2 (#3). Beta-arrestin activation of ERK1/2 MAPK, in turn, increases the translocation of transcription factors (#4) into the nucleus to influence gene transcription (#5).