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J Biol Chem, Vol. 273, Issue 16, 9804-9811, April 17, 1998

Mechanisms Involved in the Acidosis Enhancement of the Isoproterenol-induced Phosphorylation of Phospholamban in the Intact Heart

From the Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900 La Plata, Argentina

Previous experiments have shown that acidosis enhances isoproterenol-induced phospholamban (PHL) phosphorylation (Mundiña-Weilenmann, C., Vittone, L., Cingolani, H. E., Orchard, C. H. (1996) Am. J. Physiol. 270, C107-C114). In the present experiments, performed in isolated Langendorff perfused rat hearts, phosphorylation site-specific antibodies to PHL combined with the quantitative measurement of ³²P incorporation into PHL were used as experimental tools to gain further insight into the mechanism involved in this effect. At all isoproterenol concentrations tested (3-300 nM), phosphorylation of Thr¹⁷ of PHL was significantly higher at pH_o 6.80 than at pH_o 7.40, without significant changes in Ser¹⁶ phosphorylation. This increase in Thr¹⁷ phosphorylation was associated with an enhancement of the isoproterenol-induced relaxant effect. In the absence of isoproterenol, the increase in [Ca]_o at pH_o 6.80 (but not at pH_o 7.40) evoked an increase in PHL phosphorylation that was exclusively due to an increase in Thr¹⁷ phosphorylation and that was also associated with a significant relaxant effect. This effect and the phosphorylation of Thr¹⁷ evoked by acidosis were both offset by the Ca²⁺/calmodulin-dependent protein kinase II inhibitor KN-62. In the presence of isoproterenol, either the increase in [Ca]_o or the addition of a 1 µM concentration of the phosphatase inhibitor okadaic acid was able to mimic the increase in isoproterenol-induced Thr¹⁷ phosphorylation produced by acidosis. In contrast, these two interventions have opposite effects on phosphorylation of Ser¹⁶. Whereas the increase in [Ca]_o significantly decreased phosphorylation of Ser¹⁶, the addition of okadaic acid significantly increased the phosphorylation of this residue. The results are consistent with the hypothesis that the increase in phospholamban phosphorylation produced by acidosis in the presence of isoproterenol is the consequence of two different mechanisms triggered by acidosis: an increase in [Ca²⁺]_i and an inhibition of phosphatases.

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