Figure 3.

Physiological and pathological effects of cardiac βAR signalling. Norepinephrine and epinephrine, the endogenous βAR agonists, activate both β₁AR and β₂AR subtypes, albeit with different potencies. In general, β₁AR is coupled to Gα_s and β₂AR is coupled to both Gα_s and Gα_i. In the short term, the activation of β₁AR/β₂AR through Gα_s generates positive chronotropic and inotropic responses; however, chronic activation through Gα_s can induce cardiomyocyte apoptosis and hypertrophy. In contrast, Gα_i-mediated signalling via β₂AR is thought to be cardioprotective due to its anti-apoptotic and anti-fibrotic effects. Furthermore, both receptor subtypes can couple to β-arrestin, which also induces cardioprotective signalling cascades in the heart. Carvedilol, a clinically utilized β-arrestin-biased ligand, preferentially stimulates β-arrestin signalling while antagonizing G protein signalling. Notably, carvedilol-mediated β-arrestin-dependent cardioprotection is potentiated by Compound 6, a positive allosteric modulator of the β₁AR and β₂AR. Additionally, in response to agonist, Compound 6 potentiates G protein and β-arrestin signalling mediated by β₂AR, but not β₁AR. As expected, traditional antagonists such as metoprolol or propranolol, block βAR signalling via both G protein and β-arrestin. Figure generated with biorender.com.