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Conventional protein kinase C isoforms and cross-activation of protein kinase A regulate cardiac Na+ current
1Department of Pharmacology, Vanderbilt University School of Medicine, Room 559 Preston Research Building, 23rd and Pierce Avenues, Nashville, TN 37232-6602, USA.
Abstract:
We tested the hypothesis that specific isoforms of protein kinase C (PKC) are responsible for modulation of Na+ current (I(Na)) derived from the human cardiac Na+ channel using activators and inhibitors selective for specific PKCs. Experimental results demonstrated that I(Na) suppression was mediated by activation of conventional PKCs (cPKCs) and possibly resulted from channel internalization. In the presence of cPKC inhibition, phorbol ester application unexpectedly increased Na+ current, an effect eliminated by inhibition of protein kinase A. These findings demonstrate complex modulation of cardiac I(Na) by protein kinases and provide further evidence that PKC isoforms have distinct protein targets.
Insights
Specific protein kinase C (PKC) isoforms distinctly regulate cardiac sodium current (I(Na)). Conventional PKCs suppress I(Na), while other isoforms may enhance it, revealing complex kinase-mediated cardiac channel modulation.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Cell Signaling
Background:
- Cardiac sodium current (I(Na)) is critical for heart electrical activity.
- Protein kinase C (PKC) is implicated in cardiac function, but isoform-specific roles in I(Na) modulation are unclear.
Purpose of the Study:
- To investigate the distinct roles of specific protein kinase C (PKC) isoforms in modulating human cardiac sodium current (I(Na)).
- To elucidate the mechanisms underlying PKC-mediated regulation of cardiac I(Na).
Main Methods:
- Utilized isoform-selective activators and inhibitors of PKC.
- Measured I(Na) in human cardiac sodium channels.
- Investigated effects of PKC inhibition and activation on I(Na).
- Assessed the role of protein kinase A (PKA) in observed effects.
Main Results:
- Activation of conventional PKCs (cPKCs) suppressed I(Na), potentially via channel internalization.
- Inhibition of cPKCs, followed by phorbol ester application, unexpectedly increased I(Na).
- This unexpected increase in I(Na) was abolished by inhibiting protein kinase A (PKA).
Conclusions:
- Cardiac I(Na) is complexly modulated by different protein kinases.
- PKC isoforms exhibit distinct targets and functions in regulating cardiac sodium channels.
- Findings highlight the differential roles of PKC and PKA in cardiac electrophysiology.