Modulation of cytosolic and intra-sarcoplasmic reticulum calcium
waves by calsequestrin in rat cardiac myocytes.
J. Physiol., 561 (Pt 2):
515--524 (December 2004)DOI: 10.1113/jphysiol.2004.073940
Abstract
Waves of Ca$^2+$-induced Ca$^2+$ release occur in various
cell types and are involved in the pathology of certain forms of
cardiac arrhythmia. These arrhythmias include catecholaminergic polymorphic
ventricular tachycardia (CPVT), certain cases of which are associated
with mutations in the cardiac calsequestrin gene (CASQ2). To explore
the mechanisms of Ca$^2+$ wave generation and unravel the underlying
causes of CPVT, we investigated the effects of adenoviral-mediated
changes in CASQ2 protein levels on the properties of cytosolic and
sarcoplasmic reticulum (SR) Ca$^2+$ waves in permeabilized rat
ventricular myocytes. The free Ca$^2+$ inside the sarcoplasmic
reticulum (Ca$^2+$SR) was monitored by fluo-5N entrapped into
the SR, and cytosolic Ca$^2+$ was imaged using fluo-3. Overexpression
of CASQ2 resulted in significant increases in the amplitude of Ca$^2+$
waves and interwave intervals, whereas reduced CASQ2 levels caused
drastic reductions in the amplitude and period of Ca$^2+$ waves.
CASQ2 abundance had no impact on resting diastolic Ca$^2+$SR
or on the amplitude of the Ca$^2+$SR depletion signal during
the Ca$^2+$ wave. However, the recovery dynamics of Ca$^2+$SR
following Ca$^2+$ release were dramatically altered as the rate
of Ca$^2+$SR recovery increased approximately 3-fold in CASQ2-overexpressing
myocytes and decreased to 30\% of control in CASQ2-underexpressing
myocytes. There was a direct linear relationship between Ca$^2+$
wave period and the half-time of basal Ca$^2+$SR recovery following
Ca$^2+$ release. Loading the SR with the low affinity exogenous
Ca$^2+$ buffer citrate exerted effects quantitatively similar
to those observed on overexpressing CASQ2. We conclude that free
intra-SR Ca$^2+$ is a critical determinant of cardiac Ca$^2+$
wave generation. Our data indicate that reduced intra-SR Ca$^2+$
binding activity promotes the generation of Ca$^2+$ waves by
accelerating the dynamics of attaining a threshold free Ca$^2+$SR
required for Ca$^2+$ wave initiation, potentially accounting
for arrhythmogenesis in CPVT linked to mutations in CASQ2.
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