AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction

Madeline Nieves-Cintrón, Dinesh Hirenallur-Shanthappa, Patrick J. Nygren, Simon A. Hinke, Mark L. Dell'Acqua, Lorene K. Langeberg, Manuel Navedo, Luis F. Santana, John D. Scott

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The Ca2+-responsive phosphatase calcineurin/protein phosphatase 2B dephosphorylates the transcription factor NFATc3. In the myocardium activation of NFATc3 down-regulates the expression of voltage-gated K+ (Kv) channels after myocardial infarction (MI). This prolongs action potential duration and increases the probability of arrhythmias. Although recent studies infer that calcineurin is activated by local and transient Ca2+ signals the molecular mechanism that underlies the process is unclear in ventricular myocytes. Here we test the hypothesis that sequestering of calcineurin to the sarcolemma of ventricular myocytes by the anchoring protein AKAP150 is required for acute activation of NFATc3 and the concomitant down-regulation of Kv channels following MI. Biochemical and cell based measurements resolve that approximately 0.2% of the total calcineurin activity in cardiomyocytes is associated with AKAP150. Electrophysiological analyses establish that formation of this AKAP150-calcineurin signaling dyad is essential for the activation of the phosphatase and the subsequent down-regulation of Kv channel currents following MI. Thus AKAP150-mediated targeting of calcineurin to sarcolemmal micro-domains in ventricular myocytes contributes to the local and acute gene remodeling events that lead to the down-regulation of Kv currents.

Original languageEnglish (US)
Pages (from-to)733-740
Number of pages8
JournalCellular Signalling
Volume28
Issue number7
DOIs
StatePublished - Jul 1 2016

Keywords

  • A-kinase anchoring protein AKAP
  • Acute transcriptional response
  • Calcineurin
  • Myocardial infarction

ASJC Scopus subject areas

  • Cell Biology

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