Dataset Information

Regulation of Ca2+/calmodulin kinase II by a small C-terminal domain phosphatase.

ABSTRACT: We present here the identification and characterization of an SCP3 (small C-terminal domain phosphatase-3) homologue in smooth muscle and show, for the first time, that it dephosphorylates CaMKII [Ca(2+)/CaM (calmodulin)-dependent protein kinase II]. SCP3 is a PP2C (protein phosphatase 2C)-type phosphatase that is primarily expressed in vascular smooth muscle tissues and specifically binds to the association domain of the CaMKIIgamma G-2 variant. The dephosphorylation is site-specific, excluding the Thr(287) associated with Ca(2+)/CaM-independent activation of the kinase. As a result, the autonomous activity of CaMKIIgamma G-2 is not affected by the phosphatase activity of SCP3. SCP3 co-localizes with CaMKIIgamma G-2 on cytoskeletal filaments, but is excluded from the nucleus in differentiated vascular smooth muscle cells. Upon depolarization-induced Ca(2+) influx, CaMKIIgamma G-2 is activated and dissociates from SCP3. Subsequently, CaMKIIgamma G-2 is targeted to cortical adhesion plaques. We show here that SCP3 regulates phosphorylation sites in the catalytic domain, but not those involved in regulation of kinase activation. This selective dephosphorylation by SCP3 creates a constitutively active kinase that can then be differentially regulated by other phosphorylation-dependent regulatory mechanisms.

SUBMITTER: Gangopadhyay SS

PROVIDER: S-EPMC2724867 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Regulation of Ca2+/calmodulin kinase II by a small C-terminal domain phosphatase.

Gangopadhyay Samudra S SS Gallant Cynthia C Sundberg Eric J EJ Lane William S WS Morgan Kathleen G KG

The Biochemical journal 20080601 3

We present here the identification and characterization of an SCP3 (small C-terminal domain phosphatase-3) homologue in smooth muscle and show, for the first time, that it dephosphorylates CaMKII [Ca(2+)/CaM (calmodulin)-dependent protein kinase II]. SCP3 is a PP2C (protein phosphatase 2C)-type phosphatase that is primarily expressed in vascular smooth muscle tissues and specifically binds to the association domain of the CaMKIIgamma G-2 variant. The dephosphorylation is site-specific, excluding ...[more]

PMID: 18338982

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Project description:Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite more than a decade of investigation. Posttranslational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel posttranslational modifications and disease. We recently identified a novel pathway for posttranslational regulation of the primary cardiac voltage-gated Na(+) channel (Na(v)1.5) by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, a role for this pathway in cardiac disease has not been evaluated.We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Na(v)1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Na(v)1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that the human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Na(v)1.5, resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel, resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large-animal model of acquired heart disease and in failing human myocardium.We identify the mechanism for 2 human arrhythmia variants that affect Na(v)1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Na(v)1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Na(v)1.5 in congenital and acquired cardiac disease.

Dataset Information

Regulation of Ca2+/calmodulin kinase II by a small C-terminal domain phosphatase.

Publications

Regulation of Ca2+/calmodulin kinase II by a small C-terminal domain phosphatase.

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