Mutation of the Calmodulin Binding Motif IQ of the L-type Ca(v)1.2 Ca2+ Channel to EQ Induces Dilated Cardiomyopathy and Death

作者：Blaich Anne; Pahlavan Sara; Tian Qinghai; Oberhofer Martin; Poomvanicha Montatip; Lenhardt Peter; Domes Katrin; Wegener Joerg W; Moosmang Sven; Ruppenthal Sandra; Scholz Anke; Lipp Peter; Hofmann Franz^*

来源：Journal of Biological Chemistry, 2012, 287(27): 22616-22625.

DOI：10.1074/jbc.M112.357921

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 Ca(v)1.2 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 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 Cav1.2(I1624E) channel showed %26quot;CDI%26quot; 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 reducedDCMin Cav1.2(I1624E) hearts at day 10. Weconclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death.

• 出版日期2012-6-29