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[PMID]: | 29025768 |
[Au] Autor: | Sirish P; Ledford HA; Timofeyev V; Thai PN; Ren L; Kim HJ; Park S; Lee JH; Dai G; Moshref M; Sihn CR; Chen WC; Timofeyeva MV; Jian Z; Shimkunas R; Izu LT; Chiamvimonvat N; Chen-Izu Y; Yamoah EN; Zhang XD |
[Ad] Endereço: | From the Division of Cardiovascular Medicine, Department of Internal Medicine (P.S., H.A.L., V.T., P.N.T., L.R., S.P., G.D., M.M., C.-R.S., W.C.C., M.V.T., N.C., Y.C.-I., X.-D.Z.), Center for Neuroscience (H.J.K.), Department of Pharmacology (Z.J., R.S., L.T.I., N.C., Y.C.-I.) and Department of Biom |
[Ti] Título: | Action Potential Shortening and Impairment of Cardiac Function by Ablation of . |
[So] Source: | Circ Arrhythm Electrophysiol;10(10), 2017 Oct. | [Is] ISSN: | 1941-3084 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | BACKGROUND: Intracellular pH (pH ) is critical to cardiac excitation and contraction; uncompensated changes in pH impair cardiac function and trigger arrhythmia. Several ion transporters participate in cardiac pH 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 exchange activities in cardiomyocytes, suggesting the potential role of Slc26a6 in regulation of not only pH , but also cardiac excitability. METHODS AND RESULTS: To test the mechanistic role of Slc26a6 in the heart, we took advantage of knockout ( ) mice using both in vivo and in vitro analyses. Consistent with our prediction of its electrogenic activities, ablation of results in action potential shortening. There are reduced Ca transient and sarcoplasmic reticulum Ca load, together with decreased sarcomere shortening in cardiomyocytes. These abnormalities translate into reduced fractional shortening and cardiac contractility at the in vivo level. Additionally, pH is elevated in cardiomyocytes with slower recovery kinetics from intracellular alkalization, consistent with the Cl /HCO exchange activities of Slc26a6. Moreover, 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 transporter in ventricular myocytes, linking the critical roles of Slc26a6 in regulation of pH , excitability, and contractility. pH is a critical regulator of other membrane and contractile proteins. Future studies are needed to investigate possible changes in these proteins in mice. |
[Mh] Termos MeSH primário: |
Potenciais de Ação Antiporters/deficiência Acoplamento Excitação-Contração Frequência Cardíaca Contração Miocárdica Miócitos Cardíacos/metabolismo
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[Mh] Termos MeSH secundário: |
Animais Antiporters/genética Bradicardia/genética Bradicardia/metabolismo Bradicardia/fisiopatologia Células CHO Cricetulus Genótipo Concentração de Íons de Hidrogênio Cinética Proteínas de Membrana Transportadoras/genética Proteínas de Membrana Transportadoras/metabolismo Camundongos da Linhagem 129 Camundongos Knockout Fenótipo Sarcômeros/metabolismo Retículo Sarcoplasmático/metabolismo Transfecção
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Antiporters); 0 (Membrane Transport Proteins); 0 (SLC26A6 protein, human); 0 (Slc26a6 protein, mouse) |
[Em] Mês de entrada: | 1710 |
[Cu] Atualização por classe: | 171101 |
[Lr] Data última revisão:
| 171101 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 171014 |
[St] Status: | MEDLINE |
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