title: Mutation of the calmodulin binding motif IQ of the L-type Ca(v)1.2 Ca2+ channel to EQ induces dilated cardiomyopathy and death.
abstract: 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.
authors.affiliation: Forschergruppe, Institut für Pharmakologie und Toxikologie, Technische Universität München, 80802 München, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Blaich
authors.forename: Sara
authors.initials: S
authors.lastname: Pahlavan
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Tian
authors.forename: Martin
authors.initials: M
authors.lastname: Oberhofer
authors.forename: Montatip
authors.initials: M
authors.lastname: Poomvanicha
authors.forename: Peter
authors.initials: P
authors.lastname: Lenhardt
authors.forename: Katrin
authors.initials: K
authors.lastname: Domes
authors.forename: Jörg W
authors.initials: JW
authors.lastname: Wegener
authors.forename: Sven
authors.initials: S
authors.lastname: Moosmang
authors.forename: Sandra
authors.initials: S
authors.lastname: Ruppenthal
authors.forename: Anke
authors.initials: A
authors.lastname: Scholz
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D002216:Captopril / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D002478:Cells, Cultured; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D015996:Survival Rate
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000889:Anti-Arrhythmia Agents; C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D002147:Calmodulin; D002216:Captopril; D008790:Metoprolol; D002118:Calcium