Physical and functional interaction between calcineurin and the cardiac L-type Ca2+ channel.
The L-type Ca(2+) channel (LTCC) is the major mediator of Ca(2+) influx in cardiomyocytes, leading to both mechanical contraction and activation of signaling cascades. Among these Ca(2+)-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 alpha(1)1.2. 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 alpha(1)1.2. Channel function was increased in voltage-clamp recordings of I(Ca,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 I(Ca,L). These data reveal direct physical interaction between the LTCC and calcineurin in heart. Furthermore, they demonstrate that calcineurin induces robust increases in I(Ca,L) and highlight calcineurin as a key modulator of pathological electrical remodeling in cardiac hypertrophy.
Tandan
Samvit
S
Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390-8573, USA.
Wang
Yanggan
Y
Wang
Thomas T
TT
Jiang
Nan
N
Hall
Duane D
DD
Hell
Johannes W
JW
Luo
Xiang
X
Rothermel
Beverly A
BA
Hill
Joseph A
JA
D000818:Animals; D001665:Binding Sites; D019703:Calcineurin / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D006332:Cardiomegaly; D002478:Cells, Cultured; D022062:Electrophysiologic Techniques, Cardiac; D006352:Heart Ventricles / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats
D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D011494:Protein Kinases; D019703:Calcineurin