Ion channels can form complexes with solute transporters, termed “chansporters”. This interaction may be physiologically relevant in cardiac channelopathies including short QT syndrome (SQTS). SQTS is classically linked to gain-of-function mutations in hERG and K v 7. 1 channels, which shorten the cardiac action potentials and increase the risk of syncope, ventricular arrhythmias, and sudden death. More recently, mutations in the SLC4A3 gene, encoding the Cl − /HCO 3 − electroneutral exchanger AE3, have been associated with SQTS, though the underlying mechanism remains unclear. We hypothesized that AE3 may participate in ion channel-transporter interactions that influence cardiac repolarization. In this study, we identified a novel SLC4A3 mutation (c. 3290 G>A; p. G1070D) in a 35-year-old male with presyncope and a QTc interval of 340-360 ms. We investigated its functional consequences with two complementary approaches. First, heterologous expression of AE3 with hERG or K v 7. 1-MinK in HEK cells, followed by co-immunoprecipitation, demonstrated physical interactions between AE3 and both potassium channels. Patch-clamp recordings in bicarbonate-free conditions, where AE3 remains inactive, revealed that AE3ₚ. G1070D enhanced potassium channel activity by lowering activation thresholds. Second, in independent experiments with AE3 expressed alone, NH 4 Cl-based pHi recovery assays showed that AE3ₚ. G1070D had impaired acid-loading capacity. In summary, AE3 forms chansporter complexes with cardiac potassium channels, and the AE3ₚ. G1070D variant promotes a gain-of-function of repolarizing currents while producing a loss of function of the exchanger itself. Together, these dual effects may contribute to the pathophysiology of SQTS and provide new mechanistic insight into this arrhythmogenic disorder.
Carreras et al. (Sun,) studied this question.