(A) The normal atrial action potential (transmembrane potential as a function of time, in black) has a stable resting value close to –80 mV. Cell firing causes rapid depolarization (phase 0) to a positive value. Following initial repolarization, there is a flat (plateau) phase and then repolarization back to the resting potential. Normal atrial cells remain at the resting potential until they are fired through the SA node pacemaking system. Abnormal atrial automaticity results from spontaneous diastolic depolarization to a threshold value for activation. (B and C) Afterdepolarizations: abnormal membrane depolarizations after completion of the AP. DADs occur after full repolarization (B); EADs precede full repolarization (C). (D) Fundamental mechanisms leading to DADs, the most important source of ectopic activity in AF. DADs result from spontaneous diastolic SR Ca²⁺ releases through channels called RyR2s. RyR2s are sensitive to intra-SR free Ca²⁺ concentration. Abnormal diastolic RyR2 Ca²⁺ releases can result from excess SR intraluminal Ca²⁺ (pumped into the SR by SERCA) or reduced SR Ca²⁺ binding by the principal SR Ca²⁺ buffer, calsequestrin (CSQ). RyR2 hyperphosphorylation increases sensitivity to SR Ca²⁺, causing abnormal RyR2 Ca²⁺ release events. Diastolic RyR2 Ca²⁺ release increases cytosolic Ca²⁺, which has to be removed by the NCX. NCX moves three Na⁺ ions into the cell in exchange for each Ca²⁺ ion moved out, creating an inward movement of positive charges that produces a depolarizing I_ti. Repolarizing conductances oppose I_ti, protecting against excessive diastolic membrane voltage oscillations.