We provided a demonstration of the following: (1) the expression of KCa3.1 in macrophage increased significantly in the LA and RA of dogs after prolonged rapid atrial pacing, and down-regulated by TRAM-34; (2) inhibition of KCa3.1 channels decreased the vulnerability to AF after prolonged rapid atrial pacing and attenuated macrophage pro-inflammatory polarization and inflammation; (3) the effects of inhibition of KCa3.1 on AF vulnerability are probably associated with macrophage activation and the pro-inflammatory p38 MAPK/AP-1/NF-κB signaling pathway. Here, JUN is linked to atrial fibrillation.