Ca2+ wave probability is determined by the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content

Mathis K. Stokke; Sarah J. Briston; Guro F. Jølle; Isma Manzoor; William E. Louch; Leiv Øyehaug; Geir Christensen; David A. Eisner; Andrew W. Trafford; Ole M. Sejersted; Ivar Sjaastad

doi:10.1093/cvr/cvr013

Ca2+ wave probability is determined by the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content

Mathis K. Stokke, Sarah J. Briston, Guro F. Jølle, Isma Manzoor, William E. Louch, Leiv Øyehaug, Geir Christensen, David A. Eisner, Andrew W. Trafford, Ole M. Sejersted, Ivar Sjaastad

Research output: Contribution to journal › Article › peer-review

Abstract

Aims In this manuscript, we determined the roles of the sarcoendoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and the ryanodine receptor (RyR) in Ca2+ wave development during β-adrenergic stimulation. Methods and results SERCA2 knockout mice (KO) were used 6 days after cardio-specific gene deletion, with left ventricular SERCA2a abundance reduced by 54 ± 9% compared with SERCA2flox/flox controls (FF) (P <0.05). Ca 2+ waves occurred in fewer KO than FF myocytes (40 vs. 68%, P <0.05), whereas the addition of isoproterenol (ISO) induced waves in an equal percentage of myocytes (82 vs. 64%). SERCA2-dependent Ca2+ reuptake was slower in KO (-ISO, KO vs. FF: 15.4 ± 1.2 vs. 21.1 ± 1.4 s-1, P <0.05), but equal during ISO (ISO, KO vs. FF: 21.9 ± 3.3 vs. 27.7 ± 2.7 s-1). Threshold SR Ca2+ content for wave development was lower in KO (-ISO, KO vs. FF: 126.6 ± 10.3 vs. 159.3 ± 7.1 mol/L, P <0.05) and was increased by ISO only in FF (ISO, KO vs. FF: 131.7 ± 8.7 vs. 205.5 ± 20.4 mol/L, P <0.05). During ISO, Ca2+/calmodulin-dependent kinase II (CaMKII)-dependent phosphorylation of RyR in KO was 217 ± 21% of FF (P <0.05), and SR Ca2+ leak indicated higher RyR open probability in KO. CaMKII inhibition decreased Ca2+ spark frequency in KO by 44% (P <0.05) but not in FF. Mathematical modelling predicted that increased Ca2+ sensitivity of RyR in KO could account for increased Ca 2+ wave probability during ISO. Conclusions In ventricular cardiomyocytes with reduced SERCA2 abundance, Ca2+ wave development following β-adrenergic stimulation is potentiated. We suggest that this is caused by a CaMKII-dependent shift in the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content. © The Author 2011.

Original language	English
Pages (from-to)	503-512
Number of pages	9
Journal	Cardiovascular research
Volume	90
Issue number	3
DOIs	https://doi.org/10.1093/cvr/cvr013
Publication status	Published - 1 Jun 2011

Keywords

β-adrenergic stimulation
Arrhythmias
Ca2+ homeostasis
RyR
SERCA2

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10.1093/cvr/cvr013

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Stokke, M. K., Briston, S. J., Jølle, G. F., Manzoor, I., Louch, W. E., Øyehaug, L., Christensen, G., Eisner, D. A., Trafford, A. W., Sejersted, O. M., & Sjaastad, I. (2011). Ca2+ wave probability is determined by the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content. Cardiovascular research, 90(3), 503-512. https://doi.org/10.1093/cvr/cvr013

@article{83dadd8586b84da8b8a1e15bb0cbc956,

title = "Ca2+ wave probability is determined by the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content",

abstract = "Aims In this manuscript, we determined the roles of the sarcoendoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and the ryanodine receptor (RyR) in Ca2+ wave development during β-adrenergic stimulation. Methods and results SERCA2 knockout mice (KO) were used 6 days after cardio-specific gene deletion, with left ventricular SERCA2a abundance reduced by 54 ± 9% compared with SERCA2flox/flox controls (FF) (P <0.05). Ca 2+ waves occurred in fewer KO than FF myocytes (40 vs. 68%, P <0.05), whereas the addition of isoproterenol (ISO) induced waves in an equal percentage of myocytes (82 vs. 64%). SERCA2-dependent Ca2+ reuptake was slower in KO (-ISO, KO vs. FF: 15.4 ± 1.2 vs. 21.1 ± 1.4 s-1, P <0.05), but equal during ISO (ISO, KO vs. FF: 21.9 ± 3.3 vs. 27.7 ± 2.7 s-1). Threshold SR Ca2+ content for wave development was lower in KO (-ISO, KO vs. FF: 126.6 ± 10.3 vs. 159.3 ± 7.1 mol/L, P <0.05) and was increased by ISO only in FF (ISO, KO vs. FF: 131.7 ± 8.7 vs. 205.5 ± 20.4 mol/L, P <0.05). During ISO, Ca2+/calmodulin-dependent kinase II (CaMKII)-dependent phosphorylation of RyR in KO was 217 ± 21% of FF (P <0.05), and SR Ca2+ leak indicated higher RyR open probability in KO. CaMKII inhibition decreased Ca2+ spark frequency in KO by 44% (P <0.05) but not in FF. Mathematical modelling predicted that increased Ca2+ sensitivity of RyR in KO could account for increased Ca 2+ wave probability during ISO. Conclusions In ventricular cardiomyocytes with reduced SERCA2 abundance, Ca2+ wave development following β-adrenergic stimulation is potentiated. We suggest that this is caused by a CaMKII-dependent shift in the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content. {\textcopyright} The Author 2011.",

keywords = "β-adrenergic stimulation, Arrhythmias, Ca2+ homeostasis, RyR, SERCA2",

author = "Stokke, {Mathis K.} and Briston, {Sarah J.} and J{\o}lle, {Guro F.} and Isma Manzoor and Louch, {William E.} and Leiv {\O}yehaug and Geir Christensen and Eisner, {David A.} and Trafford, {Andrew W.} and Sejersted, {Ole M.} and Ivar Sjaastad",

year = "2011",

month = jun,

day = "1",

doi = "10.1093/cvr/cvr013",

language = "English",

volume = "90",

pages = "503--512",

journal = "Cardiovascular research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "3",

}

TY - JOUR

T1 - Ca2+ wave probability is determined by the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content

AU - Stokke, Mathis K.

AU - Briston, Sarah J.

AU - Jølle, Guro F.

AU - Manzoor, Isma

AU - Louch, William E.

AU - Øyehaug, Leiv

AU - Christensen, Geir

AU - Eisner, David A.

AU - Trafford, Andrew W.

AU - Sejersted, Ole M.

AU - Sjaastad, Ivar

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Aims In this manuscript, we determined the roles of the sarcoendoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and the ryanodine receptor (RyR) in Ca2+ wave development during β-adrenergic stimulation. Methods and results SERCA2 knockout mice (KO) were used 6 days after cardio-specific gene deletion, with left ventricular SERCA2a abundance reduced by 54 ± 9% compared with SERCA2flox/flox controls (FF) (P <0.05). Ca 2+ waves occurred in fewer KO than FF myocytes (40 vs. 68%, P <0.05), whereas the addition of isoproterenol (ISO) induced waves in an equal percentage of myocytes (82 vs. 64%). SERCA2-dependent Ca2+ reuptake was slower in KO (-ISO, KO vs. FF: 15.4 ± 1.2 vs. 21.1 ± 1.4 s-1, P <0.05), but equal during ISO (ISO, KO vs. FF: 21.9 ± 3.3 vs. 27.7 ± 2.7 s-1). Threshold SR Ca2+ content for wave development was lower in KO (-ISO, KO vs. FF: 126.6 ± 10.3 vs. 159.3 ± 7.1 mol/L, P <0.05) and was increased by ISO only in FF (ISO, KO vs. FF: 131.7 ± 8.7 vs. 205.5 ± 20.4 mol/L, P <0.05). During ISO, Ca2+/calmodulin-dependent kinase II (CaMKII)-dependent phosphorylation of RyR in KO was 217 ± 21% of FF (P <0.05), and SR Ca2+ leak indicated higher RyR open probability in KO. CaMKII inhibition decreased Ca2+ spark frequency in KO by 44% (P <0.05) but not in FF. Mathematical modelling predicted that increased Ca2+ sensitivity of RyR in KO could account for increased Ca 2+ wave probability during ISO. Conclusions In ventricular cardiomyocytes with reduced SERCA2 abundance, Ca2+ wave development following β-adrenergic stimulation is potentiated. We suggest that this is caused by a CaMKII-dependent shift in the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content. © The Author 2011.

AB - Aims In this manuscript, we determined the roles of the sarcoendoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and the ryanodine receptor (RyR) in Ca2+ wave development during β-adrenergic stimulation. Methods and results SERCA2 knockout mice (KO) were used 6 days after cardio-specific gene deletion, with left ventricular SERCA2a abundance reduced by 54 ± 9% compared with SERCA2flox/flox controls (FF) (P <0.05). Ca 2+ waves occurred in fewer KO than FF myocytes (40 vs. 68%, P <0.05), whereas the addition of isoproterenol (ISO) induced waves in an equal percentage of myocytes (82 vs. 64%). SERCA2-dependent Ca2+ reuptake was slower in KO (-ISO, KO vs. FF: 15.4 ± 1.2 vs. 21.1 ± 1.4 s-1, P <0.05), but equal during ISO (ISO, KO vs. FF: 21.9 ± 3.3 vs. 27.7 ± 2.7 s-1). Threshold SR Ca2+ content for wave development was lower in KO (-ISO, KO vs. FF: 126.6 ± 10.3 vs. 159.3 ± 7.1 mol/L, P <0.05) and was increased by ISO only in FF (ISO, KO vs. FF: 131.7 ± 8.7 vs. 205.5 ± 20.4 mol/L, P <0.05). During ISO, Ca2+/calmodulin-dependent kinase II (CaMKII)-dependent phosphorylation of RyR in KO was 217 ± 21% of FF (P <0.05), and SR Ca2+ leak indicated higher RyR open probability in KO. CaMKII inhibition decreased Ca2+ spark frequency in KO by 44% (P <0.05) but not in FF. Mathematical modelling predicted that increased Ca2+ sensitivity of RyR in KO could account for increased Ca 2+ wave probability during ISO. Conclusions In ventricular cardiomyocytes with reduced SERCA2 abundance, Ca2+ wave development following β-adrenergic stimulation is potentiated. We suggest that this is caused by a CaMKII-dependent shift in the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content. © The Author 2011.

KW - β-adrenergic stimulation

KW - Arrhythmias

KW - Ca2+ homeostasis

KW - RyR

KW - SERCA2

U2 - 10.1093/cvr/cvr013

DO - 10.1093/cvr/cvr013

M3 - Article

C2 - 21242164

SN - 0008-6363

VL - 90

SP - 503

EP - 512

JO - Cardiovascular research

JF - Cardiovascular research

IS - 3

ER -

Ca2+ wave probability is determined by the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content

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Keywords

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