Key result
Cav1.2 I1624E mutation in mice induces dilated cardiomyopathy and death by preventing calcium-dependent inactivation.
Survival and normal cardiac function depend on the expression of native Cav1.2 protein, as mutation of its IQ motif leads to fatal dilated cardiomyopathy.
Intact Cav1.2 IQ motif prevents fatal cardiomyopathy in mice; leaves open whether similar defects contribute to human disease.
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 Ca 2+ /calmodulin (CaM). CaM binds to the IQ motif located in the C terminus of the Ca v 1.2 channel and induces Ca 2+ -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 Ca v 1.2 I1624E mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca v 1.2 L2 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 Ca v 1.2 I1624E hearts, the activity of phospho-CaM kinase II and phospho-MAPK was increased. CMs expressed reduced levels of Ca v 1.2 I1624E channel protein and I Ca . The Ca v 1.2 I1624E channel showed "CDI" kinetics. Despite a lower sarcoplasmic reticulum Ca 2+ content, cellular contractility and global Ca 2+ 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 Ca v 1.2 I1624E 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 Ca v 1.2 channel. Results: Cardiac-specific expression of Ca v 1.2 EQ prevents CDI and CDF, reduces I Ca , and induces dilated cardiomyopathy. Conclusion: The cardiac-specific EQ mutation leads to premature death. Significance: Survival depends on the expression of a native Ca v 1.2 protein.
No takes yet. Share an insight, caveat, or question.
Blaich et al. (2012) studied Dilated cardiomyopathy. Cav1.2 I1624E (IQ to EQ) mutation was evaluated on Dilated cardiomyopathy and death. Cardiac-specific expression of the Cav1.2 I1624E (IQ to EQ) mutation in adult mice prevents calcium-dependent inactivation and facilitation, inducing dilated cardiomyopathy and premature death.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: