Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6

Padmini Sirish, Hannah A. Ledford, Valeriy Timofeyev, Phung N. Thai, Lu Ren, Hyo Jeong Kim, Seojin Park, Jeong Han Lee, Gu Dai, Maryam Moshref, Choong Ryoul Sihn, Wei Chun Chen, Maria Valeryevna Timofeyeva, Zhong Jian, Rafael Shimkunas, Leighton T. Izu, Nipavan Chiamvimonvat, Ye Chen-Izu, Ebenezer N. Yamoah, Xiao Dong Zhang

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Abstract

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.

Original languageEnglish (US)
JournalCirculation. Arrhythmia and electrophysiology
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2017

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Keywords

  • action potential
  • bradycardia
  • chloride-bicarbonate antiporters
  • myocardial contraction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Sirish, P., Ledford, H. A., Timofeyev, V., Thai, P. N., Ren, L., Kim, H. J., Park, S., Lee, J. H., Dai, G., Moshref, M., Sihn, C. R., Chen, W. C., Timofeyeva, M. V., Jian, Z., Shimkunas, R., Izu, L. T., Chiamvimonvat, N., Chen-Izu, Y., Yamoah, E. N., & Zhang, X. D. (2017). Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6. Circulation. Arrhythmia and electrophysiology, 10(10). https://doi.org/10.1161/CIRCEP.117.005267