Background: Intracellular pH (pHi) is critical to cardiac excitation and contraction; uncompensated changes in pHi impair cardiac function and trigger arrhythmia. Several ion transporters participate in cardiac pHi 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-/HCO3- exchange activities in cardiomyocytes, suggesting the potential role of Slc26a6 in regulation of not only pHi, but also cardiac excitability.
Methods and results: To test the mechanistic role of Slc26a6 in the heart, we took advantage of Slc26a6 knockout (Slc26a6-/- ) mice using both in vivo and in vitro analyses. Consistent with our prediction of its electrogenic activities, ablation of Slc26a6 results in action potential shortening. There are reduced Ca2+ transient and sarcoplasmic reticulum Ca2+ load, together with decreased sarcomere shortening in Slc26a6-/- cardiomyocytes. These abnormalities translate into reduced fractional shortening and cardiac contractility at the in vivo level. Additionally, pHi is elevated in Slc26a6-/- cardiomyocytes with slower recovery kinetics from intracellular alkalization, consistent with the Cl-/HCO3- exchange activities of Slc26a6. Moreover, Slc26a6-/- 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-/HCO3- transporter in ventricular myocytes, linking the critical roles of Slc26a6 in regulation of pHi, excitability, and contractility. pHi is a critical regulator of other membrane and contractile proteins. Future studies are needed to investigate possible changes in these proteins in Slc26a6-/- mice.
Keywords: action potential; bradycardia; chloride-bicarbonate antiporters; myocardial contraction.
© 2017 American Heart Association, Inc.