The Arrhythmogenic Calmodulin Mutation D129G Dysregulates Cell Growth, Calmodulin-dependent Kinase II Activity, and Cardiac Function in Zebrafish.
Calmodulin (CaM) is a Ca2+binding protein modulating multiple targets, several of which are associated with cardiac pathophysiology. Recently, CaM mutations were linked to heart arrhythmia. CaM is crucial for cell growth and viability, yet the effect of the arrhythmogenic CaM mutations on cell viability, as well as heart rhythm, remains unknown, and only a few targets with relevance for heart physiology have been analyzed for their response to mutant CaM. We show that the arrhythmia-associated CaM mutants support growth and viability of DT40 cells in the absence of WT CaM except for the long QT syndrome mutant CaM D129G. Of the six CaM mutants tested (N53I, F89L, D95V, N97S, D129G, and F141L), three showed a decreased activation of Ca2+/CaM-dependent kinase II, most prominently the D129G CaM mutation, which was incapable of stimulating Thr286autophosphorylation. Furthermore, the CaM D129G mutation led to bradycardia in zebrafish and an arrhythmic phenotype in a subset of the analyzed zebrafish.
From the Department of Biology and mabe@bio.ku.dk.
Martin W
http://orcid.org/0000-0001-8995-9047
MW
Berchtold
From the Department of Biology and.
Triantafyllos
T
Zacharias
the Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark, and.
Katarzyna
K
Kulej
the Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California 90095.
Kevin
K
Wang
From the Department of Biology and.
Raffaela
R
Torggler
the Danish Arrhythmia Research Centre, University of Copenhagen, 2100 Copenhagen, Denmark.
Thomas
http://orcid.org/0000-0001-6575-360X
T
Jespersen
the Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California 90095.
Jau-Nian
http://orcid.org/0000-0001-8807-3607
JN
Chen
the Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark, and.
Martin R
http://orcid.org/0000-0001-6203-0123
MR
Larsen
From the Department of Biology and jonas@bio.ku.dk.
Jonas M
JM
la Cour
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D006801:Humans; D008133:Long QT Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011487:Protein Conformation; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
D002147:Calmodulin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
Ca2+/calmodulin-dependent protein kinase II (CaMKII); DT40; calcium; calmodulin (CaM); catecholaminergic polymorphic ventricular tachycardia (CPVT); cell signaling; heart failure