Abstract
The Na +/Ca 2+ exchanger (NCX) is the primary Ca 2+ extrusion mechanism in cardiomyocytes. To further investigate the role of NCX in excitation–contraction coupling and Ca 2+ homeostasis, we created murine models with altered expression levels of NCX. Homozygous overexpression of NCX resulted in mild cardiac hypertrophy. Decline of the Ca 2+ transient and relaxation of contraction were increased and the reverse mode of NCX was augmented. Overexpression also led to a higher susceptibility to ischemia–reperfusion injury and to a greater ability of NCX to trigger Ca 2+-induced Ca 2+ release. Furthermore, an increase in peak L-type Ca 2+ current was observed suggesting a direct influence of NCX on L-type Ca 2+ current. Whereas global knockout of NCX led to prenatal death, a recently generated cardiac-specific NCX knockout mouse was viable with surprisingly normal contractile properties. Expression levels of other Ca 2+-handling proteins were not altered. Ca 2+ influx in these animals is limited by a decrease of peak L-type Ca 2+ current. An alternative Ca 2+ efflux mechanism, presumably the plasma membrane Ca 2+-ATPase, is sufficient to maintain Ca 2+-homeostasis in the NCX knockout mice.
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