Figure 8. Remodeling of I_Ca,L and inward-rectifier K⁺ currents by AF/tachycardia.

(A) The high atrial rate in AF increases intracellular Ca²⁺ load, activating calcineurin via the Ca²⁺/calmodulin system. Calcineurin stimulates nuclear translocation of nuclear factor of activated T lymphocytes (NFAT), reducing transcription of the principal I_Ca,L subunit, Cav1.2. Increased mRNA degradation/impaired protein translation of Cav1.2 and breakdown of Cav1.2 protein by calpains may also contribute. Increased expression of zinc transporter–1 (ZnT-1) impairs membrane trafficking of Cav1.2. Reduced Cav1.2 phosphorylation due to increased protein phosphatase (PP) activity and increased channel nitrosylation may also decrease I_Ca,L. GSH, glutathione. (B) Increased I_K1 density results from upregulation of the principle Kir2.1 subunit, likely due to reduced levels of inhibitory miRNAs (miR-101, miR-26, miR-1). Increased I_K,AChc is caused by altered PKC regulation: increased membrane abundance of stimulatory PKCε and reduced expression of inhibitory PKCα.