ADRB2 encodes a G protein-coupled receptor for catecholamines that activates bifurcated signaling through both G(s) and G(i) proteins. The receptor binds epinephrine with approximately 30-fold greater affinity than norepinephrine. In the heart, ADRB2 signaling through the G(s)/PKA pathway regulates myocyte contractility, while epinephrine-induced G(i) coupling provides cardioprotective effects during hypoxia and oxidative stress via PI3K/Akt signaling. ADRB2 also modulates cellular pH independently of PKA by regulating the Na+/H+ exchanger. Beyond cardiac function, ADRB2 has emerged as a central node in diverse physiological processes. Endothelial ADRB2 signaling controls angiogenesis through metabolic reprogramming in the tumor microenvironment 1, while sympathetic nerve-derived noradrenaline acting on melanocyte stem cell ADRB2 drives stress-induced hair greying through rapid stem cell proliferation and depletion 2. In human brown adipose tissue, contrary to rodent models, thermogenesis is primarily mediated by β2-AR rather than β3-AR signaling 3. Clinically, ADRB2 variants associate with respiratory disease susceptibility in preterm infants and modulate bronchodilator responsiveness in COPD patients 4. Recent evidence suggests ADRB2 inhibition suppresses cancer immune evasion by reducing PD-L1 expression through a SOX10-dependent mechanism, with potential to enhance checkpoint inhibitor efficacy in melanoma and colorectal cancer 5. Beta-blockers targeting ADRB2 represent a pharmacological approach to mitigate stress-induced immunosuppression. Additionally, the gut microbiota metabolite phenylacetylglutamine acts as a negative allosteric modulator of ADRB2, mechanistically linking microbiota composition to cardiovascular disease 6.