Abstract 17681: Functional Role of Slc26a6 in the Regulation of Cardiac Excitability
Background: One of the major knowledge gaps in cardiac physiology is the mechanism underlying the relatively high intracellular chloride concentration ([Cl−]i) in cardiomyocytes (~20-30 mM) compared to that in skeletal muscle (~4-5 mM) and the relative contribution of Cl− to cardiac excitability. Due to the passive distribution of Cl− through Cl−channels, the coupled inward Cl− transport must exist in cardiomyocytes to maintain the relatively high [Cl−]i. We recently identified and cloned the cardiac isoforms of a solute carrier, slc26a6. We demonstrated that slc26a6 mediated electrogenic Cl−/oxalate and Cl−/HCO3− exchanges in both atrial and ventricular myocytes. Since slc26a6 is electrogenic, we hypothesize that the exchange activity may regulate cardiac excitability.
Methods and Results: We recorded the resting membrane potential (RMP) and action potential (AP) in mouse ventricular myocytes using perforated patch-clamp and fast solution exchange techniques. A low extracellular Cl− concentration ([Cl−]o, 8 mM) hyperpolarized the RMP and the effect was reversible when the solution with high [Cl−]o (154 mM) was applied. The inhibition of slc26a6 hyperpolarized the RMP at high [Cl−]o. Indeed, this observation cannot be explained by the passive Cl− distribution across the cell membrane since the low [Cl−]o should depolarize the RMP if the resting Cl− conductance is significant. Moreover, AP duration was shortened by low [Cl−]o which may be explained by the enhanced HCO3−influx coupled with the Cl− efflux through slc26a6 with a stoichiometry of HCO3− : Cl− ≥ 2. We further tested the dose-dependent activation by oxalate because of the specific Cl−/oxalate exchange activities of cardiac slc26a6. The AP shortening by oxalate influx, as well as the [Cl−]o-dependent changes of RMP suggest important functional roles of slc26a6 in the regulation of cardiac excitability.
Conclusion: Cardiac slc26a6 participates in the regulation of cardiac excitability by affecting the Cl− distribution across the plasma membrane of cardiomyocytes through its electrogenic Cl−/HCO3− exchange activities. This new insight helps to pave the way for the understanding of the roles of Cl− in cardiac excitability.
Funded by AHA Western States Affiliate (14BGIA18870087 to XZ).
Author Disclosures: R.E. Myers: None. H. Ledford: None. V.C. Lau: None. H. Kim: None. C. Kim: None. X. Zhang: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.