β‐Adrenergic Blockers Increase cAMP and Stimulate Insulin Secretion Through a PKA / RYR2 / TRPM5 Pathway in Pancreatic β‐Cells In Vitro

β‐adrenergic blockers (β‐blockers) are extensively used to inhibit β‐adrenoceptor activation and subsequent cAMP production in many cell types. In this study, we characterized the effects of β‐blockers on mouse pancreatic β‐cells. Unexpectedly, high concentrations (100 μM) of β‐blockers (propranolol and bisoprolol) paradoxically increased cAMP levels 5–10 fold, enhanced Ca ²⁺ influx, and stimulated a 2–4 fold increase in glucose‐ and glimepiride‐induced insulin secretion in MIN6‐K8 clonal β‐cells and isolated mouse pancreatic islets. These effects were observed despite minimal expression of β‐adrenoceptors in these cells. Mechanistically, the cAMP increase led to ryanodine receptor 2 (RYR2) phosphorylation via protein kinase A (PKA), triggering Ca ²⁺ ‐induced Ca ²⁺ release (CICR). CICR then activates transient receptor potential cation channel subfamily M member 5 (TRPM5), resulting in increased Ca ²⁺ influx via voltage‐dependent Ca ²⁺ channels. These effects contradict the conventional understanding of the pharmacology of β‐blockers, highlighting the variability in β‐blocker actions depending on the experimental context.