Phospholamban-to-SERCA2 ratio controls the force-frequency relationship

The force-frequency relationship (FFR) describes the frequency-dependent po tentiation of cardiac contractility. The interaction of the sarcoplasmic re ticulum Ca2+-adenosinetriphosphatase (SERCA2) with its inhibitory protein p hospholamban (PLB) might be involved in the control of the FFR. The FFR was analyzed in two systems in which the PLB-to-SERCA2 ratio was modulated. Ad ult rabbit cardiac myocytes were transduced with adenovirus encoding for SE RCA2, PLB, and beta-galadosidase (control). After 3 days, the relative PLB/ SERCA2 values were significantly different between groups (SERCA2, 0.5; con trol, 1.0; PLB, 4.5). SERCA2 overexpression shortened relaxation by 23% rel ative to control, whereas PLB prolonged relaxation by 39% and reduced contr actility by 47% (0.1 Hz). When the stimulation frequency was increased to 1 .5 Hz, myocyte contractility was increased by 30% in control myocytes. PLB- overexpressing myocytes showed an augmented positive FFR (+78%), whereas SE RCA2-transduced myocytes displayed a negative FFR (-15%). A more negative F FR was also found in papillary muscles from SERCA2 transgenic mice. These f indings demonstrate that the ratio of phospholamban to SERCA2 is an importa nt component in the control of the FFR.