A-kinase anchoring protein targeting of protein kinase A and regulation of HERG channels

Yan Li, Jakub Sroubek, Yamini Krishnan, Thomas V. McDonald

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Adrenergic stimulation of the heart initiates a signaling cascade in cardiac myocytes that increases the concentration of cAMP. Although cAMP elevation may occur over a large area of a target-organ cell, its effects are often more restricted due to local concentration of its main effector, protein kinase A (PKA), through A-kinase anchoring proteins (AKAPs). The HERG potassium channel, which produces the cardiac rapidly activating delayed rectifying K + current (IKr), is a target for cAMP/PKA regulation. PKA regulation of the current may play a role in the pathogenesis of hereditary and acquired abnormalities of the channel leading to cardiac arrhythmia. We examined the possible role for AKAP-mediated regulation of HERG channels. Here, we report that the PKA-RII-specific AKAP inhibitory peptide AKAP-IS perturbs the distribution of PKA-RII and diminishes the PKA-dependent phosphorylation of HERG protein. The functional consequence of AKAP-IS is a reversal of cAMP-dependent regulation of HERG channel activity. In further support of AKAP-mediated targeting of kinase to HERG, PKA activity was coprecipitated from HERG expressed in HEK cells. Velocity gradient centrifugation of solubilized porcine cardiac membrane proteins showed that several PKA-RI and PKA-RII binding proteins cosediment with ERG channels. A physical association of HERG with several specific AKAPs with known cardiac expression, however, was not demonstrable in heterologous cotransfection studies. These results suggest that one or more AKAP(s) targets PKA to HERG channels and may contribute to the acute regulation of IKr by cAMP.

Original languageEnglish (US)
Pages (from-to)107-116
Number of pages10
JournalJournal of Membrane Biology
Volume223
Issue number2
DOIs
StatePublished - May 2008

Keywords

  • AKAP
  • HERG
  • PKA
  • Phosphorylation
  • Potassium channel
  • Protein interaction

ASJC Scopus subject areas

  • Biophysics
  • Physiology
  • Cell Biology

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