Overexpression of SERCA2b in the heart leads to an increase in sarcoplasmic reticulum calcium transport function and increased cardiac contractility

The sarcoplasmic reticulum calcium ATPase SERCA2b is an alternate isoform e ncoded by the SERCA2 gene. SERCA2b is expressed ubiquitously and has a high er Ca2+ affinity compared with SERCA2 a. We made transgenic mice that overe xpress the rat SERCA2b cDNA in the heart. SERCA2b mRNA level was approximat ely similar to 20-fold higher than endogenous SERCA2b mRNA in transgenic he arts. SERCA2b protein was increased 8-10-fold in the heart, whereas SERCA2a mRNA/protein level remained unchanged. Confocal microscopy showed that SER CA2b is localized preferentially around the T-tubules of the SR, whereas SE RCA2a isoform is distributed both transversely and longitudinally in the SR membrane. Calcium-dependent calcium uptake measurements showed that the ma ximal velocity of Ca2+ uptake was not changed, but the apparent pump affini ty for Ca2+ (K-0.5) was increased in SERCA2b transgenic mice (0.199 +/- 0.0 11 mu M) compared with wild-type control mice (0.269 +/- 0.012 mu M, p < 0. 01). Work-performing heart preparations showed that SERCA2b transgenic hear ts had a higher rates of contraction and relaxation, shorter time to peak p ressure and half-time for relaxation than wild-type hearts. These data show that SERCA2b is associated in a subcompartment within the sarcoplasmic ret iculum of cardiac myocytes. Overexpression of SERCA2b leads to an increase in SR calcium transport function and increased cardiac contractility, sugge sting that SERCA2b plays a highly specialized role in regulating the beat-t o-beat contraction of the heart.