Activation of protein kinase A modulates trafficking of the human cardiac sodium channel in Xenopus oocytes

Jingsong Zhou, Jianxun Yi, Ning Ning Hu, Alfred L. George, Katherine T. Murray*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Voltage-gated Na+ channels are critical determinants of electrophysiological properties in the heart. Stimulation of β- adrenergic receptors, which activate cAMP-dependent protein kinase (protein kinase A [PKA]), can alter impulse conduction in normal tissue and promote development of cardiac arrhythmias in pathological states. Recent studies demonstrate that PKA activation increases cardiac Na+ currents, although the mechanism of this effect is unknown. To explore the molecular basis of Na+ channel modulation by β-adrenergic receptors, we have examined the effects of PKA activation on the recombinant human cardiac Na+ channel, hHI. Both in the absence and the presence of hβ1 subunit coexpression, activation of PKA caused a slow increase in Na+ current that did not saturate despite kinase stimulation for 1 hour. In addition, there was a small shift in the voltage dependence of channel activation and inactivation to more negative voltages. Chloroquine and monensin, compounds that disrupt plasma membrane recycling, reduced hill current, suggesting rapid turnover of channels at the cell surface. Preincubation with these agents also prevented the PKA- mediated rise in Na+ current, indicating that this effect likely resulted from an increased number of Na+ channels in the plasma membrane. Experiments using chimeric constructs of hH1 and the skeletal muscle Na+ channel, hSKM1, identified the I-II interdomain loop of hill as the region responsible for the PKA effect. These results demonstrate that activation of PKA modulates both trafficking and function of the hill channel. With changes in Na+ current that could either speed or slow conduction, depending on the physiological circumstances.

Original languageEnglish (US)
Pages (from-to)33-38
Number of pages6
JournalCirculation research
Volume87
Issue number1
DOIs
StatePublished - Jul 7 2000

Keywords

  • Heart
  • Protein kinases
  • Sodium channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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