Action Potential Shortening and Impairment of Cardiac Function by Ablation of .

Background: Intracellular pH (pH) is critical to cardiac excitation and contraction; uncompensated changes in pH impair cardiac function and trigger arrhythmia. Several ion transporters participate in cardiac pH regulation. Our previous studies identified several isoforms of a solute carrier Slc26a6 to be highly expressed in cardiomyocytes. We show that Slc26a6 mediates electrogenic Cl/HCO exchange activities in cardiomyocytes, suggesting the potential role of Slc26a6 in regulation of not only pH, but also cardiac excitability.

Methods And Results: To test the mechanistic role of Slc26a6 in the heart, we took advantage of knockout ( ) mice using both in vivo and in vitro analyses. Consistent with our prediction of its electrogenic activities, ablation of results in action potential shortening. There are reduced Ca transient and sarcoplasmic reticulum Ca load, together with decreased sarcomere shortening in cardiomyocytes. These abnormalities translate into reduced fractional shortening and cardiac contractility at the in vivo level. Additionally, pH is elevated in cardiomyocytes with slower recovery kinetics from intracellular alkalization, consistent with the Cl/HCO exchange activities of Slc26a6. Moreover, mice show evidence of sinus bradycardia and fragmented QRS complex, supporting the critical role of Slc26a6 in cardiac conduction system.

Conclusions: Our study provides mechanistic insights into Slc26a6, a unique cardiac electrogenic Cl/HCO transporter in ventricular myocytes, linking the critical roles of Slc26a6 in regulation of pH, excitability, and contractility. pH is a critical regulator of other membrane and contractile proteins. Future studies are needed to investigate possible changes in these proteins in mice.