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 language | English (US) |
|---|---|
| Journal | Circulation. Arrhythmia and electrophysiology |
| Volume | 10 |
| Issue number | 10 |
| DOIs | |
| State | Published - 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
Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6. / Sirish, Padmini; Ledford, Hannah A.; Timofeyev, Valeriy; Thai, Phung N.; Ren, Lu; Kim, Hyo Jeong; Park, Seojin; Lee, Jeong Han; Dai, Gu; Moshref, Maryam; Sihn, Choong Ryoul; Chen, Wei Chun; Timofeyeva, Maria Valeryevna; Jian, Zhong; Shimkunas, Rafael; Izu, Leighton T.; Chiamvimonvat, Nipavan; Chen-Izu, Ye; Yamoah, Ebenezer N.; Zhang, Xiao Dong.
In: Circulation. Arrhythmia and electrophysiology, Vol. 10, No. 10, 01.10.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6
AU - Sirish, Padmini
AU - Ledford, Hannah A.
AU - Timofeyev, Valeriy
AU - Thai, Phung N.
AU - Ren, Lu
AU - Kim, Hyo Jeong
AU - Park, Seojin
AU - Lee, Jeong Han
AU - Dai, Gu
AU - Moshref, Maryam
AU - Sihn, Choong Ryoul
AU - Chen, Wei Chun
AU - Timofeyeva, Maria Valeryevna
AU - Jian, Zhong
AU - Shimkunas, Rafael
AU - Izu, Leighton T.
AU - Chiamvimonvat, Nipavan
AU - Chen-Izu, Ye
AU - Yamoah, Ebenezer N.
AU - Zhang, Xiao Dong
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
KW - action potential
KW - bradycardia
KW - chloride-bicarbonate antiporters
KW - myocardial contraction
UR - http://www.scopus.com/inward/record.url?scp=85031850485&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031850485&partnerID=8YFLogxK
U2 - 10.1161/CIRCEP.117.005267
DO - 10.1161/CIRCEP.117.005267
M3 - Article
C2 - 29025768
AN - SCOPUS:85031850485
VL - 10
JO - Circulation: Arrhythmia and Electrophysiology
JF - Circulation: Arrhythmia and Electrophysiology
SN - 1941-3149
IS - 10
ER -