Question: 

Rac1, a small GTPase of the Rho-family, which modulates reactive oxygen species (ROS) production, is involved in the development of cardiac diseases. In addition to ROS, we recently found that Rac1 overexpression leads to cytoskeletal and t-tubular remodeling in ventricular myocytes. Excitation-contraction coupling (ECC) efficiency is highly dependent on the t-tubular structure and hearts from mice expressing constitutively active Rac1 (RacET) display a significantly reduced fractional shortening. We thus wondered whether Rac1 overexpression impaired ECC.

Methods: 

Hearts of RacET were used for cell isolation. I_Ca and depolarization-evoked cytosolic Ca²⁺ transients were recorded simultaneously using combined patch-clamp and Ca²⁺ imaging techniques. ECC gain was calculated by ratioing of the I_Ca amplitude and the peak amplitude of the resulting Ca²⁺ transient.

Results: 

Although in ventricular myocytes from RacET Ca²⁺ current density was reduced over the entire voltage range, the resulting Ca²⁺ transients were enhanced. The resulting ECC gain was significantly increased in these cells. Similar to the current density, the corresponding total charge was diminished when compared to control. The fast component of I_Ca inactivation was significantly slowed down. Surprisingly, we found that the ECC gain was steeply dependent on the actual I_Ca duration enabling us to probe the I_Ca - Ca²⁺ release relationship that is central for early steps of ECC.

Conclusion: 

For the first time we could directly reveal possible compensatory mechanisms in cardiac diseases, i.e. upregulation of ECC gain. Most likely increased levels of neurohormones (and phosphorylation) are responsible for this modulation.

(This work was supported by GradUS and GK1326).