Abstract
SERCA2a is the cardiac-specific isoform of Ca2+-ATPase of the sarcoplasmic
reticulum (SR). A reduction of SERCA2a has been implicated in the
contractile dysfunction of heart failure, and partial knockout of
the SERCA2 gene (Atp2a2+/- mice) reiterated many of the features
of heart failure. Yet, mice with a mutation of Atp2a2, resulting
in full suppression of the SERCA2a isoform and expression of the
SERCA2b isoform only (SERCA2b/b), showed only moderate functional
impairment, despite a reduction by 40\% of the SERCA2 protein levels.
We examined in more detail the Ca2+ handling in isolated cardiac
myocytes from SERCA2b/b. At 0.25 Hz stimulation, the amplitude of
the Ca2+i transients, SR Ca2+ content, diastolic Ca2+i, and density
of ICaL were comparable between WT and SERCA2b/b. However, the decline
of Ca2+i was slower (t1/2 154+/-7 versus 131+/-5 ms; P<0.05). Reducing
the amplitude of the Ca2+i transient (eg, SR depletion), removed
the differences in Ca2+i decline. In contrast, increasing the Ca2+
load revealed pronounced reduction of SR Ca2+ uptake at high Ca2+i.
There was no increase in Na+-Ca2+ exchange protein or function. Theoretical
modeling indicated that in the SERCA2b/b mouse, the higher Ca2+ affinity
of SERCA2b partially compensates for the 40\% reduction of SERCA
expression. The lack of SR depletion in the SERCA2b/b may also be
related to the absence of upregulation of Na+-Ca2+ exchange. We conclude
that for SERCA isoforms with increased affinity for Ca2+, a reduced
expression level is better tolerated as Ca2+ uptake and storage are
impaired only at higher Ca2+ loads.
- animals;
- atpases,
- atpases;
- blotting,
- calcium,
- calcium-transporting
- cardiac,
- cytology/metabolism;
- exchanger,
- genetics/metabolism;
- genotype;
- heart
- isoenzymes,
- knockout;
- membrane
- metabolism
- metabolism/pharmacokinetics;
- metabolism;
- mice,
- mice;
- mutation;
- myocytes,
- physiology;
- potentials,
- reticulum
- reticulum,
- sarcoplasmic
- sodium-calcium
- ventricles,
- western;
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