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Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility.

ABSTRACT: Increased myofilament Ca(2+) sensitivity is a common attribute of many inherited and acquired cardiomyopathies that are associated with cardiac arrhythmias. Accumulating evidence supports the concept that increased myofilament Ca(2+) sensitivity is an independent risk factor for arrhythmias. This review describes and discusses potential underlying molecular and cellular mechanisms how myofilament Ca(2+) sensitivity affects cardiac excitation and leads to the generation of arrhythmias. Emphasized are downstream effects of increased myofilament Ca(2+) sensitivity: altered Ca(2+) buffering/handling, impaired energy metabolism and increased mechanical stretch, and how they may contribute to arrhythmogenesis.

SUBMITTER: Huke S

PROVIDER: S-EPMC2854218 | biostudies-other | 2010 May

REPOSITORIES: biostudies-other

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Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility.

Huke Sabine S Knollmann Björn C BC

Journal of molecular and cellular cardiology 20100122 5

Increased myofilament Ca(2+) sensitivity is a common attribute of many inherited and acquired cardiomyopathies that are associated with cardiac arrhythmias. Accumulating evidence supports the concept that increased myofilament Ca(2+) sensitivity is an independent risk factor for arrhythmias. This review describes and discusses potential underlying molecular and cellular mechanisms how myofilament Ca(2+) sensitivity affects cardiac excitation and leads to the generation of arrhythmias. Emphasized ...[more]

PMID: 20097204

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Project description:BackgroundDilated and hypertrophic cardiomyopathy mutations in troponin can blunt effects of protein kinase A (PKA) phosphorylation of cardiac troponin I (cTnI), decreasing myofilament Ca2+-sensitivity; however this effect has never been tested for restrictive cardiomyopathy (RCM) mutants. This study explores whether an RCM cardiac troponin T mutant (cTnT-ΔE96) interferes with convergent PKA regulation and if TnT instability contributes to greatly enhanced Ca2+-sensitivity in skinned fibers.MethodsForce of contraction in skinned cardiac porcine fiber and spectroscopic studies were performed.ResultsA decrease of -0.26 and -0.25 pCa units in Ca2+-sensitivity of contraction after PKA incubation was observed for skinned fibers incorporated with WT or cTnT-ΔE96, respectively. To further assess whether cTnT-ΔE96 interferes solely with transmission of cTnI phosphorylation effects, skinned fibers were reconstituted with PKA pseudo-phosphorylated cTnI (cTnI-SS/DD.cTnC). Fibers displaced with cTnT-WT, reconstituted with cTnI-SS/DD.cTnC decreased Ca2+-sensitivity of force (pCa50=5.61) compared to control cTnI-WT.cTnC (pCa50=5.75), similarly affecting cTnT-ΔE96 (pCa50=6.03) compared to control \cTnI-WT.cTnC (pCa50=6.14). Fluorescence studies measuring cTnC(IAANS) Ca2+-affinity changes due to cTnT-ΔE96 indicated that higher complexity (thin filament) better recapitulates skinned fiber Ca2+ sensitive changes. Circular dichroism revealed reduced α-helicity and earlier thermal unfolding for cTnT-ΔE96 compared to WT.ConclusionsAlthough ineffective in decreasing myofilament Ca2+-sensitivity to normal levels, cTnT-ΔE96 does not interfere with PKA cTnI phosphorylation mediated effects; 2) cTnT-ΔE96 requires actin to increase cTnC Ca2+-affinity; and 3) deletion of E96 reduces cTnT stability, likely disrupting crucial thin filament interactions.General significanceThe pathological effect of cTnT-ΔE96 is largely manifested by dramatic myofilament Ca2+-sensitization which still persists even after PKA phosphorylation mediated Ca2+-desensitization.

Dataset Information

Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility.

Publications

Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility.

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