Interaction Between Phospholamban Depletion and pAdrenoceptor Stimulation

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In PLB-KO mice, the effect of ^-adrenoceptor stimulation appears reduced, but this is largely because of the tonic effect of phospholamban depletion on basal contraction and relaxation (23). A residual effect of catecholamines on relaxation is observed, and this is probably due to phosphorylation of troponin I, because crossing of PLB-KO mice with a strain having mutant or slow skeletal troponin abolishes the lusitropic effect of ^-adrenoceptor stimulation completely (24,25). In rabbit myocytes transfected with phospholamban antisense, it is possible to eliminate the effect of tonic stimulation of contraction by selecting a frequency (see Fig. 1) at which basal amplitude is unchanged. At this frequency, overexpression of SERCA2a or phospholamban downregu-lation does not alter the contractile response to isoproterenol, with both maximal effect and concentration dependence unchanged (16). This suggests that cAMP-dependent phosphorylation of the L-type Ca2+ channel predominates in mediating the positive inotropic effect of catecholamines. Relaxation, however, is accelerated by SERCA2a and phospholamban antisense adenoviruses at all stimulation frequencies, so that isoproterenol is acting against this background. Isoproterenol had additive effects on both viruses, but the additional effect was modest. For example, SERCA2a overexpression and maximum concentrations of isoproterenol decreased time-to-50% relaxation (R50) by 52 and 54%, respectively, compared to basal, untreated myocytes, and the combination of the two brought the overall decrease to 66% (16). Similarly, the combination of phospholamban antisense and maximum isoproterenol brought the R50 values down by 64% (16). Interestingly, the effect of a pronounced SERCA2a overexpression plus catecholamines was not different for a partial phospholamban depletion plus catecholamines. This again speaks of some intrinsic limitation that does not permit the overexpression of SERCA2a to be effective beyond a certain level.

An additional important observation was that the stimulation of SERCA2a activity decreased the threshold for the lusitropic effect of catecholamines. In untreated myocytes, the first lusitropic concentration was similar to the first inotropic one. However, the sensitivity of R50 to isoproterenol increased by approximately half a log unit after SERCA2a overexpression and by more than one log unit for phospholamban downregulation. This implies that in phospholamban antisense-treated myocytes, the acceleration of relaxation occurred at concentrations 10-fold lower than those that increased L-type Ca2+ channel activity. Because increased Ca2+ channel activity is related to arrhythmia generation (see Subheading 3.2.), this dissociation of the two would be predicted to be beneficial particularly in failing human heart, where myocyte relaxation is slowed (26). Note, however, that the failing human heart is especially sensitive to the lusitropic effect of catecholamines, even though the contractile response is reduced or absent (27).

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