| First Author | Pluteanu F | Year | 2022 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 322 |
| Issue | 3 | Pages | H427-H441 |
| PubMed ID | 35119335 | Mgi Jnum | J:322929 |
| Mgi Id | MGI:7256848 | Doi | 10.1152/ajpheart.00539.2021 |
| Citation | Pluteanu F, et al. (2022) Activation of PKC results in improved contractile effects and Ca(2+) cycling by inhibition of PP2A-B56alpha. Am J Physiol Heart Circ Physiol 322(3):H427-H441 |
| abstractText | Protein phosphatase 2A (PP2A) represents a heterotrimer that is responsible for the dephosphorylation of important regulatory myocardial proteins. This study was aimed to test whether the phosphorylation of PP2A-B56alpha at Ser(41) by PKC is involved in the regulation of myocyte Ca(2+) cycling and contraction. For this purpose, heart preparations of wild-type (WT) and transgenic mice overexpressing the nonphosphorylatable S41A mutant form (TG) were stimulated by administration of the direct PKC activator phorbol 12-myristate 13-acetate (PMA), and functional effects were studied. PKC activation was accompanied by the inhibition of PP2A activity in WT cardiomyocytes, whereas this effect was absent in TG. Consistently, the increase in the sarcomere length shortening and the peak amplitude of Ca(2+) transients after PMA administration in WT cardiomyocytes was attenuated in TG. However, the costimulation with 1 microM isoprenaline was able to offset these functional deficits. Moreover, TG hearts did not show an increase in the phosphorylation of the myosin-binding protein C after administration of PMA but was detected in corresponding WT. PMA modulated voltage-dependent activation of the L-type Ca(2+) channel (LTCC) differently in the two genotypes, shifting V1/2a by +1.5 mV in TG and by -2.4 mV in WT. In the presence of PMA, ICaL inactivation remained unchanged in TG, whereas it was slower in corresponding WT. Our data suggest that PKC-activated enhancement of myocyte contraction and intracellular Ca(2+) signaling is mediated by phosphorylation of B56alpha at Ser(41), leading to a decrease in PP2A activity.NEW & NOTEWORTHY The importance of the serine-41 phosphorylation site on B56alpha in reducing PP2A activity was demonstrated for the first time using a transgenic mutation model. Direct activation of PKC inhibits PP2A, leading to increased phosphorylation of MyBP-C in cardiomyocytes. The increased phosphorylation of contractile proteins is influenced by the PKC-phosphoB56alpha-PP2A signaling cascade resulting in improved intracellular Ca(2+) handling and enhanced contractility and relaxation. PKC-mediated inhibition of PP2A also leads to modulation of the LTCC activation and inactivation kinetics. |
