Fight or flight cardiac responses require augmentation of Ca2+ influx via Rad phosphorylation [RNAseq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE198903 | GEO | 2022/03/20
REPOSITORIES: GEO
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Project description:Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. Despite decades of investigations, predominantly focusing on ryanodine receptor and phospholamban phosphorylation, the molecular mechanisms underlying the sympathetic nervous system control of cardiac contractility remain controversial and incompletely elucidated. Here, we identify the calcium-channel inhibitor Rad as a critical component. In cardiomyocytes isolated from knock-in mice expressing Rad with alanine-substitutions of the four PKA-phosphorylated serine residues (4SA-Rad), calcium currents cannot be increased by adrenergic agonists or phosphatase inhibitor. In these mice, basal cardiac contractility, exercise capacity and heart rate are reduced, and the augmentation of contractile force by adrenergic agonists is severely blunted. Expression of mutant calcium-channel β-subunits that cannot bind Rad is sufficient to restore calcium influx and cardiac contractility in 4SA-Rad mice to levels induced by adrenergic agonists in wild-type mice, revealing a potential therapeutic approach to enhance cardiac contractility while bypassing stimulation of adrenergic receptors.
2022-09-26 | PXD033492 | Pride
Project description:Increased cardiac contractility during fight-or-flight response is caused by b-adrenergic augmentation of CaV1.2 channels. It is assumed that this iconic regulation involves phosphorylation of CaV1.2 a1/b-subunits. In transgenic murine hearts expressing fully PKA phosphorylation-deficient mutant a1C/b, this regulation persists, however, suggesting involvement of extra-channel factors. We here show that PKA up-regulates cardiac CaV1.2 channels by phosphorylating the small G-protein Rad, relieving constitutive inhibition of CaV1.2. Peroxidase-catalyzed labeling in mice hearts expressing ascorbate peroxidase conjugated-a1C or b2b with multiplexed quantitative proteomics allowed tracking of thousands of proteins in proximity of CaV1.2.
2019-11-19 | PXD014500 | Pride
Project description:Increased cardiac contractility during fight-or-flight response is caused by b-adrenergic augmentation of CaV1.2 channels. It is assumed that this iconic regulation involves phosphorylation of CaV1.2 a1/b-subunits. In transgenic murine hearts expressing fully PKA phosphorylation-deficient mutant a1C/b, this regulation persists, however, suggesting involvement of extra-channel factors. We here show that PKA up-regulates cardiac CaV1.2 channels by phosphorylating the small G-protein Rad, relieving constitutive inhibition of CaV1.2. Peroxidase-catalyzed labeling in mice hearts expressing ascorbate peroxidase conjugated-a1C or b2b with multiplexed quantitative proteomics allowed tracking of thousands of proteins in proximity of CaV1.2.
2019-11-19 | PXD014501 | Pride
Project description:Increased cardiac contractility during fight-or-flight response is caused by b-adrenergic augmentation of CaV1.2 channels. It is assumed that this iconic regulation involves phosphorylation of CaV1.2 a1/b-subunits. In transgenic murine hearts expressing fully PKA phosphorylation-deficient mutant a1C/b, this regulation persists, however, suggesting involvement of extra-channel factors. We here show that PKA up-regulates cardiac CaV1.2 channels by phosphorylating the small G-protein Rad, relieving constitutive inhibition of CaV1.2. Peroxidase-catalyzed labeling in mice hearts expressing ascorbate peroxidase conjugated-a1C or b2b with multiplexed quantitative proteomics allowed tracking of thousands of proteins in proximity of CaV1.2.
2019-11-19 | PXD014499 | Pride
Project description:Fight or flight cardiac responses require augmentation of Ca2+ influx via Rad phosphorylation [RNAseq]
| PRJNA817269 | ENA
Project description:We performed a conditional ablation of Wt1 in the myocardium of mice embryos. RNASeq analysis identified differential expression of 137 genes in the E13.5 mutant heart as compared to controls. GO functional enrichment analysis suggested that both calcium ion regulation and modulation of potassium channels are deeply altered in the mutant myocardium
2021-07-10 | GSE178220 | GEO
Project description:Many genes responsive to C. citratus oil and citronellal were stress-related and they include genes associated with adrenergic signalling/calcium channels, cGMP-PKG signaling, apoptosis, focal adhesion, ECM-receptor interaction, ubiquitin mediated proteolysis, mTOR signalling pathway, and longevity regulating pathway.
2021-06-08 | GSE176275 | GEO
Project description:This a model from the article:
Modeling beta-adrenergic control of cardiac myocyte contractility in silico.
Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD. J Biol Chem
2003 Nov 28;278(48):47997-8003 12972422
,
Abstract:
The beta-adrenergic signaling pathway regulates cardiac myocyte contractility
through a combination of feedforward and feedback mechanisms. We used systems
analysis to investigate how the components and topology of this signaling
network permit neurohormonal control of excitation-contraction coupling in the
rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling
with excitation-contraction coupling was formulated, and each subsystem was
validated with independent biochemical and physiological measurements. Model
analysis was used to investigate quantitatively the effects of specific
molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model
allowed an 85% higher rate of cyclic AMP synthesis than an equivalent
overexpression of beta 1-adrenergic receptor, and manipulating the affinity of
Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP
production. The model predicted that less than 40% of adenylyl cyclase molecules
may be stimulated under maximal receptor activation, and an experimental
protocol is suggested for validating this prediction. The model also predicted
that the endogenous heat-stable protein kinase inhibitor may enhance basal
cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of
protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the
L-type calcium channel and phospholamban were found sufficient to predict the
dominant changes in myocyte contractility, including a 2.6x increase in systolic
calcium (inotropy) and a 28% decrease in calcium half-relaxation time
(lusitropy). By performing systems analysis, the consequences of molecular
perturbations in the beta-adrenergic signaling network may be understood within
the context of integrative cellular physiology.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD. (2003) - version=1.0
The original CellML model was created by:
Geoffrey Nunns
gnunns1@jhu.edu
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
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In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230118 | BioModels
Project description:L-type voltage-gated calcium channels (LTCCs) regulate crucial physiological processes in the heart. They are composed of the Cav1 pore-forming subunit and the accessory subunits Cav, Cav2 and Cav. Cav is a cytosolic soluble protein that regulates channel trafficking and activity, but it also exerts other LTCC-independent functions. Cardiac hypertrophy, a relevant risk factor for the development of congestive heart failure, depends on the activation of calcium-dependent pro-hypertrophic signaling cascades; however, the role of LTCCs in this pathology remains controversial. Here, by using shRNA-mediated Cav silencing, we demonstrate that Cav2 downregulation enhances 1-adrenergic receptor agonist-induced cardiomyocyte hypertrophy in an LTCC-independent manner. We report that a pool of Cav2 is targeted to the nucleus in cardiomyocytes and that the expression of this nuclear fraction decreases during in vitro and in vivo induction of cardiac hypertrophy. Moreover, the overexpression of nucleus-targeted Cav2 in cardiomyocytes inhibits in vitro-induced hypertrophy. Quantitative proteomic analyses showed that Cav2 knockdown leads to changes in the expression of diverse myocyte proteins, including reduction of calpastatin, an endogenous inhibitor of the calcium-dependent protease calpain. Accordingly, Cav2-deficient cardiomyocytes had a two-fold increase in calpain activity as compared to control cells. Furthermore, inhibition of calpain activity in Cav2-deficient cells abolished the enhanced 1-adrenergic receptor agonist-induced hypertrophy observed in these cells. Our findings indicate that in cardiomyocytes, a nuclear pool of Cav2 participates in cellular functions that are independent of LTCC activity. They also indicate that a downregulation of nuclear Cav2 during cardiac hypertrophy promotes the activation of calpain-dependent hypertrophic pathways.
2021-09-09 | PXD016483 | Pride
Project description:Background: Modulation of mRNA splicing acts as an important layer of gene regulation, in addition to transcriptional regulation and epigenetic modifications. RNA binding proteins (RBPs) play essential roles in mediating RNA splicing and are key regulators of heart development and function. Our previous studies demonstrated that RBPMS (RNA-binding protein with multiple splicing) regulates cardiac development through modulating mRNA splicing during embryogenesis. Here we explored the postnatal function of RBPMS in the heart. Methods: We ablated Rbpms in the heart by generating a cardiac-specific knockout mouse line (Myh6-Cre, Rbpmsfl/fl), and evaluated its cardiac functions by histology, echocardiography, and gene expression. Paired-end RNA sequencing and RT-PCR were performed to identify and validate splicing targets of RBPMS in adult mouse hearts. Proximity-dependent Biotin Identification (BioID) assay and mass spectrometry analysis were performed to identify RBPMS binding partners. We also measured contractility and calcium fluxes in isolated mouse cardiomyocytes, and contractile forces of cardiac papillary muscle. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) were also used as a model to explore the influence of RBPMS on contractility of human cardiomyocytes. Results: he absence of Rbpms in the heart led to dilated cardiomyopathy (DCM) and heart failure, causing early death in mice. Mice with cardiac-specific knockout of Rbpms showed myocardium noncompaction with reduced cardiomyocyte number at the neonatal stage and developed DCM with pervasive myocardial fibrosis in adulthood. We found that RBPMS mediates a largely distinct RNA splicing profile in adult mouse hearts compared to neonatal hearts, indicating a stage-specific modulation of alternative RNA splicing by RBPMS. In adult hearts, RBPMS mainly influenced alternative splicing of genes associated with sarcomere structures and cardiomyocyte contraction, such as Ttn, Pdlim5 and Nexn, to generate new protein isoforms. In neonatal hearts, RBPMS influenced the splicing of cytoskeletal genes. RBMPS was associated with spliceosome factors and other RNA binding proteins that play important roles in the heart, such as RBM20 and GATA4. Importantly, we found that the absence of Rbpms caused severe cardiomyocyte contractile defects and reduced calcium sensitivity in both mouse and hiPSC-CMs. Our results demonstrated that Rbpms is crucial for postnatal cardiac function and cardiomyocyte contractility by regulating RNA alternative splicing. Conclusions: Loss of Rbpms in the heart causes reduced cardiomyocyte number and impaired cardiomyocyte contraction, leading to DCM and heart failure.
2023-11-03 | GSE218672 | GEO