Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
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Target Concepts:
Gene/Protein
Disease
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Enzyme
Compound
Query: EC:2.7.11.17 (
CaMKII
)
4,029
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Transient outward K+ current (I to) downregulation following sustained tachycardia in vivo is usually attributed to tachycardiomyopathy. This study assessed potential direct rate regulation of cardiac I(to) and underlying mechanisms. Cultured adult canine left ventricular cardiomyocytes (37 degrees C) were paced continuously at 1 or 3 Hz for 24 hours. I to was recorded with whole-cell patch clamp. The 3-Hz pacing reduced I to by 44% (P<0.01). Kv4.3 mRNA and protein expression were significantly reduced (by approximately 30% and approximately 40%, respectively) in 3-Hz paced cells relative to 1-Hz cells, but KChIP2 expression was unchanged. Prevention of Ca2+ loading with nimodipine or calmodulin inhibition with W-7,
A-7
, or W-13 eliminated 3-Hz pacing-induced I to downregulation, whereas downregulation was preserved in the presence of valsartan. Inhibition of
Ca2+/calmodulin-dependent protein kinase
(CaMK)II with KN93, or calcineurin with cyclosporin A, also prevented I to downregulation.
CaMKII
-mediated phospholamban phosphorylation at threonine 17 was increased in 3-Hz paced cells, compatible with enhanced
CaMKII
activity, with functional significance suggested by acceleration of the Ca2+i transient decay time constant (Indo 1-acetoxymethyl ester microfluorescence). Total phospholamban expression was unchanged, as was expression of Na+/Ca2+ exchange and sarcoplasmic reticulum Ca2+-ATPase proteins. Nuclear localization of the calcineurin-regulated nuclear factor of activated T cells (NFAT)c3 was increased in 3-Hz paced cells compared to 1-Hz (immunohistochemistry, immunoblot). INCA-6 inhibition of NFAT prevented I to reduction in 3-Hz paced cells. Calcineurin activity increased after 6 hours of 3-Hz pacing.
CaMKII
inhibition prevented calcineurin activation and NFATc3 nuclear translocation with 3-Hz pacing. We conclude that tachycardia downregulates I to expression, with the Ca2+/calmodulin-dependent
CaMKII
and calcineurin/NFAT systems playing key Ca2+-sensing and signal-transducing roles in rate-dependent I to control.
...
PMID:Mechanisms underlying rate-dependent remodeling of transient outward potassium current in canine ventricular myocytes. 1881 10
In rat vascular smooth muscle cells (RVSMC), 3-h Na
+
,K
+
-ATPase inhibition by ouabain or in K
+
-free medium resulted in the inversion of the [Na
+
]
i
/[K
+
]
i
ratio and elevation up to 7-fold the content of Egr1, Atf3, Nr4a1 and Ptgs2 mRNAs. Ouabain increased the rate of 45Ca
2+
influx by 2-fold that was abolished by L-type voltage-gated Ca
2+
channel blocker nicardipine, but it was resistant to Na
+
/Ca
2+
exchanger inhibitor KB-R7943. To study the role of Ca
2+
-mediated signaling in the expression of Na
+
i
/K
+
i
-sensitive genes we used intracellular Ca
2+
chelator BAPTA and incubated RVSMC in Ca
2+
-free medium. The elevation of Nr4a1 and Ptgs2 expression triggered by ouabain was diminished in Ca
2+
-depeleted cells as well as in the presence of nicardipine and calmodulin antagonists
A-7
and W-7. Ptgs2 expression was also suppressed by inhibitor of Ca
2+
/calmodulin-dependent protein kinase (
CaMKII
) KN-93 whereas increment of Nr4a1 content triggered by ouabain was attenuated by inhibitor of Ca
2+
/calmodulin-dependent protein phosphatase (calcineurin, CaN) cyclosporin A. Neither Ca
2+
depletion nor above listed compounds had any impact on the augmented expression of Egr1 and Atf3 in ouabain-treated RVSMC. Our results strongly suggest that dissipation of transmembrane gradient of monovalent cations increases Ptgs2 and Nr4a1 transcription via augment Ca
2+
influx through L-type Ca
2+
channels that, in turn, leads to
CaMKII
-mediated phosphorylation of CREB and calcineurin-mediated dephosphorylation of NFAT, respectively. Additional experiments should be performed to identify intermediates of Na
+
i
,K
+
i
-mediated Ca
2+
-independent excitation-transcription coupling involved the regulation of Egr1 and Atf3 expression.
...
PMID:Augmented gene expression triggered by Na
+
,K
+
-ATPase inhibition: Role of Ca
2+
i
-mediated and -independent excitation-transcription coupling. 2912 8
