Fight or flight cardiac responses require augmentation of Ca2+ influx via Rad phosphorylation [RNAseq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA817269 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18360764_1.fastq.gz | Fastqsanger.gz | |||
| SRR18360764_2.fastq.gz | Fastqsanger.gz | |||
| SRR18360765_1.fastq.gz | Fastqsanger.gz | |||
| SRR18360765_2.fastq.gz | Fastqsanger.gz | |||
| SRR18360766_1.fastq.gz | Fastqsanger.gz |
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Project description:One of the most recognizable physiological phenomena is the adrenergic-induced fight-or-flight increase in heart rate and cardiac contraction. For the β-adenergic agonist-induced enhancement of calcium influx and transients, and contractility in the heart, we identify the dual requirement of a subpopulation of Rad-bound calcium channels under basal conditions and PKA phosphorylation of Rad. In mice expressing a non-phosphorylatable Rad mutant, basal cardiac contractility is reduced and adrenergic-augmentation of the calcium current and contractility are disabled. Expression of mutant calcium channel β-subunits that cannot bind the mutant Rad restored contractility, revealing a highly specific therapeutic approach to mimic the contractility imparted by adrenergic agonists. Our findings place Rad and its modulation of calcium channels at the nexus of adrenergic modulation of cardiac responses.
2022-03-20 | GSE198903 | GEO
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:Honey bees move through a series of in-hive tasks (M-bM-^@M-^\nursingM-bM-^@M-^]) to outside tasks (M-bM-^@M-^\foragingM-bM-^@M-^]) that coincident with an intense increase in metabolic activity. Social context can cause worker bees to speed up, or slow down this process and foragers may revert back to their earlier in hive tasks accompanied by reversion to earlier physiological states. To determine if the transcriptional profile of forager bees can revert, or if the effects of flight on gene expression are irreversible, we used whole-genome microarrays. Brain tissue and flight muscle exhibited independent patterns of expression during behavioral transitions, with patterns of expression in the brain reflecting both age and behavior, while flight muscle exhibited primarily age-related patterns of expression. Our data suggest that the transition from little to no flight (nurse) to intense flight (forager), rather than the amount of flight has a major effect on gene expression. Following behavioral reversion there was a partial reversion in gene expression but some aspects of forager expression patterns, such as those for genes involved in immune function, remained. These data suggest an epigenetic control and energy balance role in honey bee functional senescence. Brains and thoraces from the same individuals of all behavioral groups were compared on a total of 132 arrays. The samples were hybridized against each other using a loop design. The groups tested are outlined as follows: Typical aged nurse 'YN' (8-10 days old; <1 day flight experience), Precocious forager 'PF' (8 to 10 days old; 2 to 3 days flight experience), Overaged nurse 'ON' (19 to 22 days old; < 1 day flight experience), Forager - low flight 'TFL' (19 to 22 days old; 2 to 3 days flight experience), Forager - high flight 'TFH' ( 19 to 22 days old; 7 to 9 days flight experience), Forager - old 'OF' (25 to 26 days old; 10 to 12 days flight experience), Reverted nurse 'RN' (25 to 26 days old; 7 to 9 days flight experience). The comparisons are outlined as follows: YN:ON (6 arrays), ON:RN (6 arrays), RN:TFH (6 arrays), TFH:TFL (6 arrays), TFL:PF (6 arrays), PF:YN (6 arrays), ON:TFL (12 arrays), YN:OF (6 arrays), OF:RN (6 arrays), RN:YN (6 arrays). Each comparison was done for individual brains and thoraces. Total: 132 arrays
2012-10-01 | E-GEOD-40650 | biostudies-arrayexpress
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.
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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 | PXD014500 | Pride
Project description:Honey bees move through a series of in-hive tasks (“nursing”) to outside tasks (“foraging”) that coincident with an intense increase in metabolic activity. Social context can cause worker bees to speed up, or slow down this process and foragers may revert back to their earlier in hive tasks accompanied by reversion to earlier physiological states. To determine if the transcriptional profile of forager bees can revert, or if the effects of flight on gene expression are irreversible, we used whole-genome microarrays. Brain tissue and flight muscle exhibited independent patterns of expression during behavioral transitions, with patterns of expression in the brain reflecting both age and behavior, while flight muscle exhibited primarily age-related patterns of expression. Our data suggest that the transition from little to no flight (nurse) to intense flight (forager), rather than the amount of flight has a major effect on gene expression. Following behavioral reversion there was a partial reversion in gene expression but some aspects of forager expression patterns, such as those for genes involved in immune function, remained. These data suggest an epigenetic control and energy balance role in honey bee functional senescence.
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2014-04-10 | E-GEOD-56549 | biostudies-arrayexpress