PUB - Publikationen an der Universität Bielefeld

Cardiac excitation-contraction coupling (EC coupling) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart. Calcium channels are major players of EC coupling and are regulated by voltage and Ca2+/calmodulin (CaM). CaM binds to the IQ motif located in the C terminus of the Cav1.2 channel and induces Ca2+-dependent inactivation (CDI) and facilitation (CDF). Mutation of Ile to Glu (Ile1624Glu) in the IQ motif abolished regulation of the channel by CDI and CDF. Here, we addressed the physiological consequences of such a mutation in the heart. Murine hearts expressing the Cav1.2I1624E mutation were generated in adult heterozygous mice through inactivation of the floxed WT Cav1.2L2 allele by tamoxifen-induced cardiac-specific activation of the MerCreMer Cre recombinase. Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy (DCM) accompanied by apoptosis of cardiac myocytes (CM) and fibrosis. In Cav1.2I1624E hearts, the activity of phospho-CaM kinase II and phospho-MAPK was increased. CMs expressed reduced levels of Cav1.2I1624E channel protein and ICa. The Cav1.2I1624E channel showed “CDI” kinetics. Despite a lower sarcoplasmic reticulum Ca2+ content, cellular contractility and global Ca2+ transients remained unchanged because the EC coupling gain was up-regulated by an increased neuroendocrine activity. Treatment of mice with metoprolol and captopril reduced DCM in Cav1.2I1624E hearts at day 10. We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death. Background: Mutation of the IQ motif to EQ abolished in vitro CDI and CDF of the Cav1.2 channel. Results: Cardiac-specific expression of Cav1.2EQ prevents CDI and CDF, reduces ICa, and induces dilated cardiomyopathy. Conclusion: The cardiac-specific EQ mutation leads to premature death. Significance: Survival depends on the expression of a native Cav1.2 protein.