The arrhythmogenic calmodulin mutation D129G dysregulates cell growth, calmodulin-dependent kinase II activity, and cardiac function in zebrafish

Martin Werner Berchtold; Triantafyllos Zacharias; Katarzyna Kulej; Kevin Wang; Raffaela Torggler; Thomas Jespersen; Jau Nian Chen; Martin R. Larsen; Jonas Marstrand la Cour

doi:10.1074/jbc.m116.758680

The arrhythmogenic calmodulin mutation D129G dysregulates cell growth, calmodulin-dependent kinase II activity, and cardiac function in zebrafish

Martin Werner Berchtold^*, Triantafyllos Zacharias, Katarzyna Kulej, Kevin Wang, Raffaela Torggler, Thomas Jespersen, Jau Nian Chen, Martin R. Larsen, Jonas Marstrand la Cour

^*Corresponding author for this work

9 Citations (Scopus)

Abstract

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 Thr²⁸⁶ autophosphorylation. Furthermore, the CaM D129G mutation led to bradycardia in zebrafish and an arrhythmic phenotype in a subset of the analyzed zebrafish.

Original language	English
Journal	Journal of Biological Chemistry
Volume	291
Issue number	52
Pages (from-to)	26636-26646
Number of pages	11
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.m116.758680
Publication status	Published - 2016

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Berchtold, M. W., Zacharias, T., Kulej, K., Wang, K., Torggler, R., Jespersen, T., Chen, J. N., Larsen, M. R., & la Cour, J. M. (2016). The arrhythmogenic calmodulin mutation D129G dysregulates cell growth, calmodulin-dependent kinase II activity, and cardiac function in zebrafish. Journal of Biological Chemistry, 291(52), 26636-26646. https://doi.org/10.1074/jbc.m116.758680

The arrhythmogenic calmodulin mutation D129G dysregulates cell growth, calmodulin-dependent kinase II activity, and cardiac function in zebrafish. / Berchtold, Martin Werner; Zacharias, Triantafyllos; Kulej, Katarzyna et al.

In: Journal of Biological Chemistry, Vol. 291, No. 52, 2016, p. 26636-26646.

Research output: Contribution to journal › Journal article › Research › peer-review

Berchtold, MW, Zacharias, T, Kulej, K, Wang, K, Torggler, R, Jespersen, T, Chen, JN, Larsen, MR & la Cour, JM 2016, 'The arrhythmogenic calmodulin mutation D129G dysregulates cell growth, calmodulin-dependent kinase II activity, and cardiac function in zebrafish', Journal of Biological Chemistry, vol. 291, no. 52, pp. 26636-26646. https://doi.org/10.1074/jbc.m116.758680

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title = "The arrhythmogenic calmodulin mutation D129G dysregulates cell growth, calmodulin-dependent kinase II activity, and cardiac function in zebrafish",

abstract = "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 Thr286 autophosphorylation. Furthermore, the CaM D129G mutation led to bradycardia in zebrafish and an arrhythmic phenotype in a subset of the analyzed zebrafish.",

author = "Berchtold, {Martin Werner} and Triantafyllos Zacharias and Katarzyna Kulej and Kevin Wang and Raffaela Torggler and Thomas Jespersen and Chen, {Jau Nian} and Larsen, {Martin R.} and {la Cour}, {Jonas Marstrand}",

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T1 - The arrhythmogenic calmodulin mutation D129G dysregulates cell growth, calmodulin-dependent kinase II activity, and cardiac function in zebrafish

AU - Berchtold, Martin Werner

AU - Zacharias, Triantafyllos

AU - Kulej, Katarzyna

AU - Wang, Kevin

AU - Torggler, Raffaela

AU - Jespersen, Thomas

AU - Chen, Jau Nian

AU - Larsen, Martin R.

AU - la Cour, Jonas Marstrand

PY - 2016

Y1 - 2016

N2 - 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 Thr286 autophosphorylation. Furthermore, the CaM D129G mutation led to bradycardia in zebrafish and an arrhythmic phenotype in a subset of the analyzed zebrafish.

AB - 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 Thr286 autophosphorylation. Furthermore, the CaM D129G mutation led to bradycardia in zebrafish and an arrhythmic phenotype in a subset of the analyzed zebrafish.

U2 - 10.1074/jbc.m116.758680

DO - 10.1074/jbc.m116.758680

M3 - Journal article

C2 - 27815504

AN - SCOPUS:85007308077

SN - 0021-9258

VL - 291

SP - 26636

EP - 26646

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 52

ER -

The arrhythmogenic calmodulin mutation D129G dysregulates cell growth, calmodulin-dependent kinase II activity, and cardiac function in zebrafish

Abstract

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