Year: 2017
Type: article
Abstract: Background Intracellular pH (pH i ) is critical to cardiac excitation and contraction; uncompensated changes in pH i impair cardiac function and trigger arrhythmia. Several ion transporters participate in cardiac pH i 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 3 − exchange activities in cardiomyocytes, suggesting the potential role of Slc26a6 in regulation of not only pH i , 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 Ca 2+ transient and sarcoplasmic reticulum Ca 2+ 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, pH i is elevated in Slc26a6 −/ − cardiomyocytes with slower recovery kinetics from intracellular alkalization, consistent with the Cl − /HCO 3 − 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 − /HCO 3 − transporter in ventricular myocytes, linking the critical roles of Slc26a6 in regulation of pH i , excitability, and contractility. pH i is a critical regulator of other membrane and contractile proteins. Future studies are needed to investigate possible changes in these proteins in Slc26a6 −/ − mice.
Authors: 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
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, American Heart Association, Yale University, National Institutes of Health, University of California, Davis, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute on Deafness and Other Communication Disorders, National Institute of Environmental Health Sciences
Awards: G1185946596, G1204761399, G1508866, G1852817908, G2366971526, Potassium Homeostasis in the Inner Ear, G2536180224, G2594488598, G3611106499, In Vivo Ultrasound Imaging System (VEVO 2100, VisualSonics), G5496526517, G6231172903, Translational Study of Cardiac Dysfunction, G8143743519, Training Program in Basic and Translational Cardiovascular Science, Determinants of age-induced hearing loss and reversal strategies, Functional interactions of cardiac ion channels, G900591525
OpenAlex ID: W2760875748