Protein phosphatase 2A effectively modulates basal L-type Ca(2+) current by dephosphorylating Ca(v)1.2 at serine 1866 in mouse cardiac myocytes.
Calcium (Ca(2+)) influx through Ca(v)1.2 L-type Ca(2+) channels is an important event for cardiac excitation-contraction (E-C) coupling. The functional regulation of Ca(v)1.2 is controlled by multiple kinases and phosphatases. It has been well documented that phosphorylation of Ca(v)1.2 by PKA or other kinases is sufficient for the upregulation of channel activity. However, little is known about the role of protein phosphatases in counterbalancing the phosphorylation of Ca(v)1.2, especially the degree to which protein phosphatase 2A (PP2A)-mediated dephosphorylation is involved in the regulation of Ca(v)1.2 in the mouse heart. Here, we report a physical interaction between PP2A and the C-terminus of Ca(v)1.2 in mouse heart extracts as revealed by coimmunoprecipitation. This interaction was further confirmed by the observation that PP2A and Ca(v)1.2 are colocalized in isolated mouse cardiomyocytes. Specifically, PP2A was bound at serine 1866 in the C-terminus of Ca(v)1.2, and PP2A-induced Ca(v)1.2 dephosphorylation at serine 1866 was observed in mouse cardiomyocytes. Importantly, the density of L-type calcium current increased in line with the increase in the phosphorylation at serine 1866 of Ca(v)1.2 in cardiac-specific PP2A Cα knockout mice. These phenomena were reproduced by treatment with okadaic acid, a PP2A inhibitor, in H9c2 cells. In summary, our data reveal the functional role of PP2A in cardiac Ca(v)1.2 regulation.
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210046, China.
Jie
J
Shi
Pengyu
P
Gu
Zhonghua
Z
Zhu
Jinxu
J
Liu
Zhong
Z
Chen
Xiaoli
X
Sun
Wen
W
Chen
Xiang
X
Gao
Zhao
Z
Zhang
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D012694:Serine; D054648:Protein Phosphatase 2; D002118:Calcium