PXD033492-1

PXD033492 is an original dataset announced via ProteomeXchange.

Title	Fight-or-flight responses require augmentation of Ca2+ influx via Rad phosphorylation
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.
HostingRepository	PRIDE
AnnounceDate	2022-09-26
AnnouncementXML	Submission_2022-09-26_10:41:41.165.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gary Bradshaw
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	L-methionine sulfone; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-04-28 00:37:00	ID requested
⏵ 1	2022-09-26 10:41:41	announced

Dataset with its publication pending

ProteomeXchange project tag: Cardiovascular (B/D-HPP), Biology/Disease-Driven Human Proteome Project (B/D-HPP)

submitter keyword: adrenergic, heart, calcium, ion channels, phosphorylation, contractility, PKA, mass spectrometry, phosphatases

Steven O. Marx
contact affiliation	Division of Cardiology, Department of Medicine; Columbia University, Vagelos College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032. Department of Pharmacology and Molecular Signaling, Columbia University, Vagelos College of Physicians and Surgeons
contact email	sm460@cumc.columbia.edu
lab head
Gary Bradshaw
contact affiliation	Harvard Medical School
contact email	Gary_bradshaw@hms.harvard.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/09/PXD033492

PRIDE project URI

• PRIDE
  1. PXD033492
     1. Label: PRIDE project
     2. Name: Fight-or-flight responses require augmentation of Ca2+ influx via Rad phosphorylation