Abstract
Background/Aims: The expression and regulation of Ca<sup>2+</sup> signaling in embryonic cardiomyocytes has been shown to be different from those in adult heart cells, particularly the L-type Ca<sup>2+</sup>channel current (I<sub>CaL</sub>) increases during development. However, little is known about the underlying reasons for this increase of I<sub>CaL </sub> density and developmental changes in the process of I<sub>CaL </sub> inactivation, a critical regulator of intracellular Ca<sup>2+</sup> homeostasis. In the present work, we therefore studied functional differences of I<sub>CaL </sub> between embryonic and fetal cardiomyocytes and its interaction with intracellular Ca<sup>2+</sup> homeostasis and Ca<sup>2+</sup>-induced Ca<sup>2+</sup> release (CICR). Moreover, we examined the process of voltage- (VDI) and Ca<sup>2+</sup>-dependent inactivation (CDI) of I<sub>CaL</sub> during murine embryonic heart development. Methods: The electrophysiological characteristics of I<sub>CaL </sub> inactivation were analyzed in embryonic ventricular cardiomyocytes of early (E9.5-11.5) and late developmental, fetal (LDS, E16.5-18.5) stages and of adult mice using the whole-cell patch-clamp technique. Results: Fast, Ca<sup>2+</sup>-dependent inactivation kinetics (τ<sub>f</sub>) were significantly accelerated in LDS-derived cardiomyocytes (2.53±1.43 ms, n=9) as compared to EDS (5.09±2.19 ms, n=8, p>=0.009), whereas slow, voltage-dependent inactivation time constants (&tau <sub>s</sub>) were unchanged. In cardiomyocytes derived from LDS we observed an increase in the maximal gating charge (Q<sub>max</sub>), suggesting an increase in the number of L-type Ca<sup>2+</sup> channels at the sarcolemma, whereas the channel open probability (P<sub>o</sub>) was unchanged. Accordingly a significantly higher I<sub>CaL </sub> density was found in LDS (-14±2.26 pA/pF, n=14) versus> EDS-derived cardiomyocytes (-10.03±1.43 pA/pF, n=13, p< 0.05). Since ryanodine (10 µM) failed to alter τ<sub>f</sub> at both developmental stages, a major contribution of CICR and bulk Ca<sup>2+</sup> to the acceleration of the fast inactivation kinetics during heart development seems to be unlikely. Conclusion: Our data suggest that the increase of local subsarcolemmal Ca<sup>2+</sup>, evoked by the higher expression of L-type Ca<sup>2+</sup> channels at the sarcolemma, rather than bulk Ca<sup>2+</sup> accelerates I<sub>CaL </sub> inactivation during embryonic heart development.
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