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

  • Author(s): Nieves-Cintrón, M
  • Hirenallur-Shanthappa, D
  • Nygren, PJ
  • Hinke, SA
  • Dell'Acqua, ML
  • Langeberg, LK
  • Navedo, M
  • Santana, LF
  • Scott, JD
  • et al.

Published Web Location

http://www.sciencedirect.com/science/article/pii/S0898656815300206
No data is associated with this publication.
Abstract

© 2015 Elsevier Inc. 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 Kvchannels 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 Kvchannel 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 Kvcurrents.

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