Physical and functional interaction between calcineurin and the cardiac L-Type Ca2+ Channel

Samvit Tandan, Yanggan Wang, Thomas T. Wang, Nan Jiang, Duane D. Hall, Johannes W. Hell, Xiang Luo, Beverly A Rothermel, Joseph A Hill

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

The L-type Ca2+ channel (LTCC) is the major mediator of Ca 2+ influx in cardiomyocytes, leading to both mechanical contraction and activation of signaling cascades. Among these Ca2+-activated cascades is calcineurin, a protein phosphatase that promotes hypertrophic growth of the heart. Coimmunoprecipitations from heart extracts and pulldowns using heterologously expressed proteins provided evidence for direct binding of calcineurin at both the N and C termini of α11.2. At the C terminus, calcineurin bound specifically at amino acids 1943 to 1971, adjacent to a well-characterized protein kinase (PK)A/PKC/PKG phospho-acceptor site Ser1928. In vitro assays demonstrated that calcineurin can dephosphorylate α11.2. Channel function was increased in voltage-clamp recordings of ICa,L from cultured cardiomyocytes expressing constitutively active calcineurin, consistent with previous observations in cardiac hypertrophy in vivo. Conversely, acute suppression of calcineurin pharmacologically or with specific peptides decreased ICa,L. These data reveal direct physical interaction between the LTCC and calcineurin in heart. Furthermore, they demonstrate that calcineurin induces robust increases in ICa,L and highlight calcineurin as a key modulator of pathological electrical remodeling in cardiac hypertrophy.

Original languageEnglish (US)
Pages (from-to)51-60
Number of pages10
JournalCirculation Research
Volume105
Issue number1
DOIs
StatePublished - Jul 2 2009

Fingerprint

Calcineurin
Cardiomegaly
Cardiac Myocytes
Atrial Remodeling
Phosphoprotein Phosphatases
Cyclic AMP-Dependent Protein Kinases
Amino Acids
Peptides
Growth

Keywords

  • Action potential remodeling
  • Ca
  • Calcineurin
  • Channels
  • Electrophysiology
  • Hypertrophy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Physical and functional interaction between calcineurin and the cardiac L-Type Ca2+ Channel. / Tandan, Samvit; Wang, Yanggan; Wang, Thomas T.; Jiang, Nan; Hall, Duane D.; Hell, Johannes W.; Luo, Xiang; Rothermel, Beverly A; Hill, Joseph A.

In: Circulation Research, Vol. 105, No. 1, 02.07.2009, p. 51-60.

Research output: Contribution to journalArticle

Tandan, Samvit ; Wang, Yanggan ; Wang, Thomas T. ; Jiang, Nan ; Hall, Duane D. ; Hell, Johannes W. ; Luo, Xiang ; Rothermel, Beverly A ; Hill, Joseph A. / Physical and functional interaction between calcineurin and the cardiac L-Type Ca2+ Channel. In: Circulation Research. 2009 ; Vol. 105, No. 1. pp. 51-60.
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