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Differential calcineurin/NFATc3 activity contributes to the Ito transmural gradient in the mouse heart.
- Source :
-
Circulation research [Circ Res] 2006 May 26; Vol. 98 (10), pp. 1306-13. Date of Electronic Publication: 2006 Apr 13. - Publication Year :
- 2006
-
Abstract
- Kv4 channels are differentially expressed across the mouse left ventricular free wall. Accordingly, the transient outward K+ current (Ito), which is produced by Kv4 channels, is greater in left ventricular epicardial (EPI) than in endocardial (ENDO) cells. However, the mechanisms underlying heterogeneous Kv4 expression in the heart are unclear. Here, we tested the hypothesis that differential [Ca2+]i and calcineurin/NFATc3 signaling in EPI and ENDO cells contributes to the gradient of Ito function in the mouse left ventricle. In support of this hypothesis, we found that [Ca2+]i, calcineurin, and NFAT activity were greater in ENDO than in EPI myocytes. However, the amplitude of Ito was the same in ENDO and EPI cells when [Ca2+]i, calcineurin, and NFAT activity were equalized. Consistent with this, we observed complete loss of Ito and Kv4 heterogeneity in NFATc3-null mice. Interestingly, Kv4.3, Kv4.2, and KChIP2 genes had different apparent thresholds for NFATc3-dependent suppression and were ordered as Kv4.3 approximately KChIP2>Kv4.2. Based on these data, we conclude that calcineurin and NFATc3 constitute a Ca(2+)-driven signaling module that contributes to the nonuniform distribution of Kv4 expression, and hence Ito function, in the mouse left ventricle.
- Subjects :
- Animals
Calcineurin metabolism
Calcium metabolism
Down-Regulation
Electric Conductivity
Endocardium cytology
Endocardium metabolism
Heart Ventricles metabolism
Intracellular Membranes metabolism
Kv Channel-Interacting Proteins genetics
Mice
Mice, Inbred BALB C
Mice, Knockout
Myocytes, Cardiac metabolism
NFATC Transcription Factors deficiency
NFATC Transcription Factors metabolism
Osmolar Concentration
Pericardium cytology
Pericardium metabolism
RNA, Messenger metabolism
Shal Potassium Channels genetics
Shal Potassium Channels metabolism
Signal Transduction
Calcineurin physiology
Myocardium metabolism
NFATC Transcription Factors physiology
Shal Potassium Channels physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 98
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 16614306
- Full Text :
- https://doi.org/10.1161/01.RES.0000222028.92993.10