Abstract
The sarcoplasmic reticulum calcium ATPase SERCA2b is an alternate isoform encoded by the SERCA2 gene. SERCA2b is expressed ubiquitously and has a higher Ca(2+) affinity compared with SERCA2a. We made transgenic mice that overexpress the rat SERCA2b cDNA in the heart. SERCA2b mRNA level was approximately approximately 20-fold higher than endogenous SERCA2b mRNA in transgenic hearts. SERCA2b protein was increased 8-10-fold in the heart, whereas SERCA2a mRNA/protein level remained unchanged. Confocal microscopy showed that SERCA2b is localized preferentially around the T-tubules of the SR, whereas SERCA2a isoform is distributed both transversely and longitudinally in the SR membrane. Calcium-dependent calcium uptake measurements showed that the maximal velocity of Ca(2+) uptake was not changed, but the apparent pump affinity for Ca(2+) (K(0.5)) was increased in SERCA2b transgenic mice (0.199 +/- 0.011 micrometer) compared with wild-type control mice (0.269 +/- 0.012 micrometer, p < 0.01). Work-performing heart preparations showed that SERCA2b transgenic hearts had a higher rates of contraction and relaxation, shorter time to peak pressure and half-time for relaxation than wild-type hearts. These data show that SERCA2b is associated in a subcompartment within the sarcoplasmic reticulum of cardiac myocytes. Overexpression of SERCA2b leads to an increase in SR calcium transport function and increased cardiac contractility, suggesting that SERCA2b plays a highly specialized role in regulating the beat-to-beat contraction of the heart.
Highlights
The sarco(endo)plasmic reticulum Ca2ϩ-ATPase (SERCA)1 family of proteins is encoded by three separate genes: SERCA1, SERCA2, and SERCA3
SERCA2b is found in the luminal pole, whereas SERCA3 is expressed in the basal pole
There is little change in the amount of endogenous SERCA2a protein level. This is in contrast to mice that overexpress SERCA1, in which there is a 50% down-regulation of SERCA2a protein in cardiac myocytes [16, 28]
Summary
The sarco(endo)plasmic reticulum Ca2ϩ-ATPase (SERCA) family of proteins is encoded by three separate genes: SERCA1, SERCA2, and SERCA3 Each of these genes is transcribed in a tissue-specific manner, and alternate splicing results in at least six different isoforms. By analogy to its role in other cell types, SERCA2b might be expected to play such a unique role in cardiac myocytes. No such intracellular compartmentalization or specialized role has yet been shown. Enzymatic turnover for SERCA2b in a COS expression system is about 0.5 times that of SERCA2a [11, 13] Cells must regulate their Ca2ϩ within a very tight physiological range; too little Ca2ϩ results in impaired function, and
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