Dataset Information

Control of Ca2+ release by action potential configuration in normal and failing murine cardiomyocytes.

ABSTRACT: Cardiomyocytes from failing hearts exhibit spatially nonuniform or dyssynchronous sarcoplasmic reticulum (SR) Ca(2+) release. We investigated the contribution of action potential (AP) prolongation in mice with congestive heart failure (CHF) after myocardial infarction. AP recordings from CHF and control myocytes were included in a computational model of the dyad, which predicted more dyssynchronous ryanodine receptor opening during stimulation with the CHF AP. This prediction was confirmed in cardiomyocyte experiments, when cells were alternately stimulated by control and CHF AP voltage-clamp waveforms. However, when a train of like APs was used as the voltage stimulus, the control and CHF AP produced a similar Ca(2+) release pattern. In this steady-state condition, greater integrated Ca(2+) entry during the CHF AP lead to increased SR Ca(2+) content. A resulting increase in ryanodine receptor sensitivity synchronized SR Ca(2+) release in the mathematical model, thus offsetting the desynchronizing effects of reduced driving force for Ca(2+) entry. A modest nondyssynchronous prolongation of Ca(2+) release was nevertheless observed during the steady-state CHF AP, which contributed to increased time-to-peak measurements for Ca(2+) transients in failing cells. Thus, dyssynchronous Ca(2+) release in failing mouse myocytes does not result from electrical remodeling, but rather other alterations such as T-tubule reorganization.

SUBMITTER: Louch WE

PROVIDER: S-EPMC2931738 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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Control of Ca2+ release by action potential configuration in normal and failing murine cardiomyocytes.

Louch William E WE Hake Johan J Jølle Guro Five GF Mørk Halvor K HK Sjaastad Ivar I Lines Glenn T GT Sejersted Ole M OM

Biophysical journal 20100901 5

Cardiomyocytes from failing hearts exhibit spatially nonuniform or dyssynchronous sarcoplasmic reticulum (SR) Ca(2+) release. We investigated the contribution of action potential (AP) prolongation in mice with congestive heart failure (CHF) after myocardial infarction. AP recordings from CHF and control myocytes were included in a computational model of the dyad, which predicted more dyssynchronous ryanodine receptor opening during stimulation with the CHF AP. This prediction was confirmed in ca ...[more]

PMID: 20816049

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Project description:The G(??)-sequestering peptide ?-adrenergic receptor kinase (?ARK)ct derived from the G-protein-coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP signaling has been proposed as the underlying mechanism for increased ?-adrenergic receptor (?AR) responsiveness. However, molecular targets mediating improved cardiac contractile performance by ?ARKct and its impact on G(??)-mediated signaling have yet to be fully elucidated.We sought to identify G(??)-regulated targets and signaling mechanisms conveying ?ARKct-mediated enhanced ?AR responsiveness in normal (NC) and failing (FC) adult rat ventricular cardiomyocytes.Assessing viral-based ?ARKct gene delivery with electrophysiological techniques, analysis of contractile performance, subcellular Ca²(+) handling, and site-specific protein phosphorylation, we demonstrate that ?ARKct enhances the cardiac L-type Ca²(+) channel (LCC) current (I(Ca)) both in NCs and FCs on ?AR stimulation. Mechanistically, ?ARKct augments I(Ca) by preventing enhanced inhibitory interaction between the ?1-LCC subunit (Cav1.2?) and liberated G(??) subunits downstream of activated ?ARs. Despite improved ?AR contractile responsiveness, ?ARKct neither increased nor restored cAMP-dependent protein kinase (PKA) and calmodulin-dependent kinase II signaling including unchanged protein kinase (PK)C?, extracellular signal-regulated kinase (ERK)1/2, Akt, ERK5, and p38 activation both in NCs and FCs. Accordingly, although ?ARKct significantly increases I(Ca) and Ca²(+) transients, being susceptible to suppression by recombinant G(??) protein and use-dependent LCC blocker, ?ARKct-expressing cardiomyocytes exhibit equal basal and ?AR-stimulated sarcoplasmic reticulum Ca²(+) load, spontaneous diastolic Ca²(+) leakage, and survival rates and were less susceptible to field-stimulated Ca²(+) waves compared with controls.Our study identifies a G(??)-dependent signaling pathway attenuating cardiomyocyte I(Ca) on ?AR as molecular target for the G(??)-sequestering peptide ?ARKct. Targeted interruption of this inhibitory signaling pathway by ?ARKct confers improved ?AR contractile responsiveness through increased I(Ca) without enhancing regular or restoring abnormal cAMP-signaling. ?ARKct-mediated improvement of I(Ca) rendered cardiomyocytes neither susceptible to ?AR-induced damage nor arrhythmogenic sarcoplasmic reticulum Ca²(+) leakage.

Dataset Information

Control of Ca2+ release by action potential configuration in normal and failing murine cardiomyocytes.

Publications

Control of Ca2+ release by action potential configuration in normal and failing murine cardiomyocytes.

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