Cl − /HCO 3− Exchanger slc26a6 : A pH Regulator Shapes the Cardiac Action Potential

See Article by Sirish et al Regulation of intracellular pH (pHi) is often considered a housekeeping function, contributing little to cardiac contractile activity. With the study published by Sirish et al1 in this issue of Circulation: Arrhythmia and Electrophysiology , a Cl−/HCO3− exchanger is revealed to have a more central role in the heart. pHiis an important modulator of cardiac excitation and contraction2 and can adversely contribute to electric arrhythmia.3 Correspondingly, cardiac myocytes express a complex apparatus to regulate pHi. Cardiac muscle cytosolic pH (≈7.2) is maintained by sarcolemmal ion transport proteins that move H+, OH−, or HCO3− ions across the membrane.4 Along with the acid extruders, Na+/H+ exchanger 1 and Na+/HCO3− cotransporter (NBC, electrogenic NBCe1/e2 and electroneutral NBCn1) myocytes possess Cl−/HCO3− exchangers (SLC4 family members AE1, AE2, and AE3) and Cl−/OH− exchanger (with no molecular identity) alkali extruders.4 SLC26 gene family members were identified as (mouse slc26a65 and its human orthologue SLC26A6,6 and slc26a37) responsible for Cl−/HCO3− and Cl−/OH− exchange at plasma membrane of heart ventricles.7 The work of Sirish et al1 in this issue revealed that ablation of slc26a6 , encoding a plasma membrane Cl−/HCO3− exchange protein, results in cardiac action potential (AP) shortening, cardiomyocyte Ca2+ transient and sarcoplasmic reticulum …