POPDC2 (popeye domain cAMP effector 2) is a membrane-bound cAMP-binding protein essential for cardiac pacemaking and conduction. The protein functions by binding cAMP and regulating the subcellular localization and activity of effector proteins, particularly the two-pore potassium channel TREK-1 1. POPDC2 enhances TREK-1 membrane transport and current density in a cAMP-dependent manner, with increased cAMP levels blocking this enhancement 12. The protein is highly expressed in cardiac pacemaker regions, particularly the sinoatrial and atrioventricular nodes 32. Loss-of-function mutations in POPDC2 cause autosomal recessive cardiac syndrome characterized by sinus node dysfunction, atrioventricular conduction defects, and hypertrophic cardiomyopathy 2. Heterozygous nonsense mutations contribute to familial atrioventricular block through impaired TREK-1 modulation 3. POPDC2 forms complexes with POPDC1, and pathogenic variants can destabilize this complex, reducing protein abundance 2. The protein also serves as a biomarker for cardiomyocyte-derived extracellular vesicles, enabling non-invasive cardiac monitoring 4. Additionally, POPDC2 expression is dysregulated in diabetic cardiomyopathy and certain cancers 56.