Protein phosphatase 2A effectively modulates basal L-type Ca(2+) current by dephosphorylating Ca(v)1.2 at serine 1866 in mouse cardiac myocytes.

Abstract 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.