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 F Navedo, Luis Fernando Santana, John D. Scott

Research output: Contribution to journalArticle

11 Citations (Scopus)

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

Fingerprint

Calcineurin
Muscle Cells
Down-Regulation
Myocardial Infarction
Voltage-Gated Potassium Channels
Sarcolemma
Phosphoric Monoester Hydrolases
Cardiac Myocytes
Action Potentials
Cardiac Arrhythmias
Myocardium
Transcription Factors
Genes
transcription factor NF-AT c3
Proteins

Keywords

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

ASJC Scopus subject areas

  • Cell Biology

Cite this

Nieves-Cintrón, M., Hirenallur-Shanthappa, D., Nygren, P. J., Hinke, S. A., Dell'Acqua, M. L., Langeberg, L. K., ... Scott, J. D. (2016). AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction. Cellular Signalling, 28(7), 733-740. https://doi.org/10.1016/j.cellsig.2015.12.015

AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction. / Nieves-Cintrón, Madeline; Hirenallur-Shanthappa, Dinesh; Nygren, Patrick J.; Hinke, Simon A.; Dell'Acqua, Mark L.; Langeberg, Lorene K.; Navedo, Manuel F; Santana, Luis Fernando; Scott, John D.

In: Cellular Signalling, Vol. 28, No. 7, 01.07.2016, p. 733-740.

Research output: Contribution to journalArticle

Nieves-Cintrón, Madeline ; Hirenallur-Shanthappa, Dinesh ; Nygren, Patrick J. ; Hinke, Simon A. ; Dell'Acqua, Mark L. ; Langeberg, Lorene K. ; Navedo, Manuel F ; Santana, Luis Fernando ; Scott, John D. / AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction. In: Cellular Signalling. 2016 ; Vol. 28, No. 7. pp. 733-740.
@article{7a1b438e9e364713b64740e9d0c83429,
title = "AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction",
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.",
keywords = "A-kinase anchoring protein AKAP, Acute transcriptional response, Calcineurin, Myocardial infarction",
author = "Madeline Nieves-Cintr{\'o}n and Dinesh Hirenallur-Shanthappa and Nygren, {Patrick J.} and Hinke, {Simon A.} and Dell'Acqua, {Mark L.} and Langeberg, {Lorene K.} and Navedo, {Manuel F} and Santana, {Luis Fernando} and Scott, {John D.}",
year = "2016",
month = "7",
day = "1",
doi = "10.1016/j.cellsig.2015.12.015",
language = "English (US)",
volume = "28",
pages = "733--740",
journal = "Cellular Signalling",
issn = "0898-6568",
publisher = "Elsevier Inc.",
number = "7",

}

TY - JOUR

T1 - AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction

AU - Nieves-Cintrón, Madeline

AU - Hirenallur-Shanthappa, Dinesh

AU - Nygren, Patrick J.

AU - Hinke, Simon A.

AU - Dell'Acqua, Mark L.

AU - Langeberg, Lorene K.

AU - Navedo, Manuel F

AU - Santana, Luis Fernando

AU - Scott, John D.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - A-kinase anchoring protein AKAP

KW - Acute transcriptional response

KW - Calcineurin

KW - Myocardial infarction

UR - http://www.scopus.com/inward/record.url?scp=84960926785&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960926785&partnerID=8YFLogxK

U2 - 10.1016/j.cellsig.2015.12.015

DO - 10.1016/j.cellsig.2015.12.015

M3 - Article

C2 - 26724383

AN - SCOPUS:84960926785

VL - 28

SP - 733

EP - 740

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

IS - 7

ER -