PXD045996-1

PXD045996 is an original dataset announced via ProteomeXchange.

Title	p38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia
Description	Ventricular fibrillation (VF) is a leading immediate cause of sudden cardiac death. There is a strong association between aging and VF, although the mechanisms are unclear, limiting the availability of targeted therapeutic interventions. Here we found find that the stress kinases p38 and p38/are activated in the ventricles of old mice and mice with genetic or drug-induced arrhythmogenic conditions. We discovered that upon activation, the increased activity of p38 and p38/ was cooperatively associated increase the with susceptibility to stress-induced VF. Mechanistically, our data indicate that activated p38 and p38wphosphorylatee identified ryanodine receptor 2 (RyR2) and disrupt Kv4.3 channel localization, as a new substrate of p38/. Our data indicate that phosphorylation of SAP97 by activated p38/ also disrupts Kv4.3 localization at the plasma membrane, promoting sarcoplasmic reticulum calcium leak, Ito current reduction and action potential duration prolongation. In turn, this led to aberrant intracellular calcium handling, premature ventricular complexes, and enhanced susceptibility to VF. The importance of this finding is evidenced by the fact that bBlocking this pathway protected genetically modified animals from VF development and reduced the VF duration in aged animals. We have identified p38/-driven phosphorylation of RyR2 and SAP97 as a novel trigger of VF. These results indicate that p38 and p38/ are a new potential therapeutic target for sustained VF prevention.
HostingRepository	PRIDE
AnnounceDate	2023-10-18
AnnouncementXML	Submission_2023-10-18_08:47:41.576.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Juan ALopez
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-09 07:02:32	ID requested
⏵ 1	2023-10-18 08:47:41	announced
2	2024-10-22 06:06:17	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Phosphoproteome

isobaric labelling

TMT

Juan ALopez
contact affiliation	Head, Proteomics Unit, CNIC
contact email	jalopez@cnic.es
lab head
Juan ALopez
contact affiliation	CNIC
contact email	jalopez@cnic.es
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045996
     1. Label: PRIDE project
     2. Name: p38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia