| First Author | Sirish P | Year | 2017 |
| Journal | Circ Arrhythm Electrophysiol | Volume | 10 |
| Issue | 10 | PubMed ID | 29025768 |
| Mgi Jnum | J:302778 | Mgi Id | MGI:6510117 |
| Doi | 10.1161/CIRCEP.117.005267 | Citation | Sirish P, et al. (2017) Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6. Circ Arrhythm Electrophysiol 10(10) |
| abstractText | 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 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, 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. |
