Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Valli, Haseeb; Ahmad, Shahzad; Sriharan, Sujan; Dean, Lydia; Grace, Andrew A.; Jeevaratnam, Kamalan; Matthews, Hugh R.; Huang, Christopher

doi:10.1111/1440-1681.12870

Cited by 22 publications

(27 citation statements)

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“…Thus Ca 2+ could directly bind to EF-hand intracellular motifs in Na V 1.5, bind with EF-hand motifs on Ca 2+ -calmodulin (CaM) that in turn reacts with IQ sites on Na V 1.5, or bind to CaM-dependent kinase II (CaMKII) activating its phosphorylating, inhibitory action on Na V 1.5 [59,60]. Finally, recent reports demonstrated that both genetic modifications in RyR2 [59] and acute activation of protein kinase A (PKA)-independent exchange protein increase ryanodine receptor mediated sarcoplasmic reticular Ca 2+ release [61] with reversible Na + channel effects [62]. Similarly, altered Ca 2+ homoeostasis elevating cytosolic [Ca 2+ ] leads to gap junction closure reducing intercellular coupling [63–65].…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of arrhythmic substrate in ageing murine peroxisome proliferator-activated receptor γ co-activator deficient hearts modelling mitochondrial dysfunction

et al. 2019

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Introduction: Ageing and chronic metabolic disorders are associated with mitochondrial dysfunction and cardiac pro-arrhythmic phenotypes which were recently attributed to slowed atrial and ventricular action potential (AP) conduction in peroxisome proliferator-activated receptor γ co-activator deficient (Pgc-1β−/−) mice. Methods: We compared expression levels of voltage-gated Na+ channel (NaV1.5) and gap junction channels, Connexins 40 and 43 (Cx40 and Cx43) in the hearts of young and old, and wild-type (WT) and Pgc-1β−/− mice. This employed Western blotting (WB) for NaV1.5, Cx40 and Cx43 in atrial/ventricular tissue lysates, and immunofluorescence (IF) from Cx43 was explored in tissue sections. Results were analysed using two-way analysis of variance (ANOVA) for independent/interacting effects of age and genotype. Results: In atria, increased age and Pgc-1β−/− genotype each independently decreased both Cx40 and Cx43 expression without interacting effects. In IF experiments, both age and Pgc-1β deletion independently reduced Cx43 expression. In ventricles, age and genotype exerted interacting effects in WB studies of NaV1.5 expression. Young Pgc-1β−/− then showed greater NaV1.5 expression than young WT ventricles. However, neither age nor Pgc-1β deletion affected Cx43 expression, independently or through interacting effects in both WB and IF studies. Conclusion: Similar pro-arrhythmic atrial/ventricular phenotypes arise in aged/Pgc-1β−/− from differing contributions of altered protein expression and functional effects that may arise from multiple acute mechanisms.

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Section: Discussionmentioning

confidence: 99%

Molecular basis of arrhythmic substrate in ageing murine peroxisome proliferator-activated receptor γ co-activator deficient hearts modelling mitochondrial dysfunction

et al. 2019

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“…Three hearts were studied from each group. The mice studied were littermates of animals whose hearts had undergone electrophysiological study reported elsewhere (Valli et al, 2017a,b, 2018a,b). Young mice were between the ages of 12–16 weeks old and aged mice greater than 52 weeks of age.…”

Section: Methodsmentioning

confidence: 99%

Atrial Transcriptional Profiles of Molecular Targets Mediating Electrophysiological Function in Aging and Pgc-1β Deficient Murine Hearts

et al. 2019

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Background Deficiencies in the transcriptional co-activator, peroxisome proliferative activated receptor, gamma, coactivator-1β are implicated in deficient mitochondrial function. The latter accompanies clinical conditions including aging, physical inactivity, obesity, and diabetes. Recent electrophysiological studies reported that Pgc-1 β -/- mice recapitulate clinical age-dependent atrial pro-arrhythmic phenotypes. They implicated impaired chronotropic responses to adrenergic challenge, compromised action potential (AP) generation and conduction despite normal AP recovery timecourses and background resting potentials, altered intracellular Ca 2+ homeostasis, and fibrotic change in the observed arrhythmogenicity. Objective We explored the extent to which these age-dependent physiological changes correlated with alterations in gene transcription in murine Pgc-1 β -/- atria. Methods and Results RNA isolated from murine atrial tissue samples from young (12–16 weeks) and aged (>52 weeks of age), wild type (WT) and Pgc-1β -/- mice were studied by pre-probed quantitative PCR array cards. We examined genes encoding sixty ion channels and other strategic atrial electrophysiological proteins. Pgc-1β -/- genotype independently reduced gene transcription underlying Na + -K + -ATPase, sarcoplasmic reticular Ca 2+ -ATPase, background K + channel and cholinergic receptor function. Age independently decreased Na + -K + -ATPase and fibrotic markers. Both factors interacted to alter Hcn4 channel activity underlying atrial automaticity. However, neither factor, whether independently or interactively, affected transcription of cardiac Na + , voltage-dependent K + channels, surface or intracellular Ca 2+ channels. Nor were gap junction channels, β-adrenergic receptors or transforming growth factor-β affected. Conclusion These findings limit the possible roles of gene transcriptional changes in previously reported age-dependent pro-arrhythmic electrophysiologial changes observed in Pgc-1 β -/- atria to an altered Ca 2+ -ATPase ( Atp2a2 ) expression. This directly parallels previously reported arrhythmic mechanism associated with p21-activated kinase type 1 deficiency. This could add to contributions from the direct physiological outcomes of mitochondrial dysfunction, whether through reactive oxygen species (ROS) production or altered Ca ...

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“…Dantrolene itself contrastingly produced increases in I Na . Murine cardiac muscle showed concordant effects of enhanced SR Ca 2+ release either with 8-CPT application 11 or in RyR2-P2328S genetic variants 12 .…”

Section: Introductionmentioning

confidence: 98%

Sarcoplasmic reticular Ca2+-ATPase inhibition paradoxically upregulates murine skeletal muscle Nav1.4 function

Liu

Matthews

Huang

2021

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Skeletal muscle Na+ channels possess Ca2+- and calmodulin-binding sites implicated in Nav1.4 current (INa) downregulation following ryanodine receptor (RyR1) activation produced by exchange protein directly activated by cyclic AMP or caffeine challenge, effects abrogated by the RyR1-antagonist dantrolene which itself increased INa. These findings were attributed to actions of consequently altered cytosolic Ca2+, [Ca2+]i, on Nav1.4. We extend the latter hypothesis employing cyclopiazonic acid (CPA) challenge, which similarly increases [Ca2+]i, but through contrastingly inhibiting sarcoplasmic reticular (SR) Ca2+-ATPase. Loose patch clamping determined Na+ current (INa) families in intact native murine gastrocnemius skeletal myocytes, minimising artefactual [Ca2+]i perturbations. A bespoke flow system permitted continuous INa comparisons through graded depolarizing steps in identical stable membrane patches before and following solution change. In contrast to the previous studies modifying RyR1 activity, and imposing control solution changes, CPA (0.1 and 1 µM) produced persistent increases in INa within 1–4 min of introduction. CPA pre-treatment additionally abrogated previously reported reductions in INa produced by 0.5 mM caffeine. Plots of peak current against voltage excursion demonstrated that 1 µM CPA increased maximum INa by ~ 30%. It only slightly decreased half-maximal activating voltages (V0.5) and steepness factors (k), by 2 mV and 0.7, in contrast to the V0.5 and k shifts reported with direct RyR1 modification. These paradoxical findings complement previously reported downregulatory effects on Nav1.4 of RyR1-agonist mediated increases in bulk cytosolic [Ca2+]. They implicate possible local tubule-sarcoplasmic triadic domains containing reduced [Ca2+]TSR in the observed upregulation of Nav1.4 function following CPA-induced SR Ca2+ depletion.

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Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Cited by 22 publications

References 58 publications

Molecular basis of arrhythmic substrate in ageing murine peroxisome proliferator-activated receptor γ co-activator deficient hearts modelling mitochondrial dysfunction

Molecular basis of arrhythmic substrate in ageing murine peroxisome proliferator-activated receptor γ co-activator deficient hearts modelling mitochondrial dysfunction

Atrial Transcriptional Profiles of Molecular Targets Mediating Electrophysiological Function in Aging and Pgc-1β Deficient Murine Hearts

Sarcoplasmic reticular Ca2+-ATPase inhibition paradoxically upregulates murine skeletal muscle Nav1.4 function

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