PXD042425

PXD042425 is an original dataset announced via ProteomeXchange.

Title	KCNK3 channel dysregulation in PAH
Description	Introduction. Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions. The mechanisms of dasatinib-associated PAH are still incomplete. This study studied the link between dasatinib and KCNK3 and the consequences of dasatinib exposure or KCNK3 knockdown in pulmonary endothelial cells (PECs) and pulmonary arterial smooth muscle cells (PASMC). Methods. We discovered a KCNK3 gene variant in a patient with dasatinib-associated PAH and investigated the impact of this variant on KCNK3 function using patch-clamp analysis. Additionally, we assessed the effects of dasatinib exposure on KCNK3 expression and function in human and rat pulmonary arteries. In control-human PASMCs and PECs (hPASMCs and hPECs), we evaluated the consequence of KCNK3 knockdown on cell migration, mitochondrial membrane potential, ATP production, and in vitro tube formation. Using mass spectrometry, we determined the KCNK3 interactome. Results. Patch-clamp revealed that the identified KCNK3 variant represents a loss-of-function variant. Dasatinib contributed to pulmonary artery constriction by decreasing KCNK3 function and expression. In control-hPASMCs, KCNK3 knockdown promotes mitochondrial membrane depolarization and glycolytic shift. Additionally, dasatinib exposure or KCNK3 knockdown reduced the number of caveolae in PECs. Moreover, KCNK3 knockdown in control-hPECs reduced migration, proliferation, and in vitro tubulogenesis. Lastly, using proximity ligation assay and mass spectrometry, we identified the KCNK3 interactome revealing that KCNK3 interaction with various proteins across different cellular compartments could impact these cellular functions. Conclusion. We identified a novel pathogenic variant in the KCNK3 gene, suggesting that KCNK3 gene variations could also influence the development of dasatinib-associated PAH. Our results support that one of the mechanisms of action of dasatinib-associated PAH results from the downregulation of KCNK3.
HostingRepository	PRIDE
AnnounceDate	2025-10-17
AnnouncementXML	Submission_2025-10-17_07:17:38.674.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Chiara guerrera
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-23 04:42:14	ID requested
⏵ 1	2025-10-17 07:17:39	announced

Ribeuz HL, Willer AS, Chevalier B, Sancho M, Masson B, Eyries M, Jung V, Guerrera IC, Dutheil M, Jekmek KE, Laubry L, Carpentier G, Perez-Vizcaino F, Tu L, Guignabert C, Chaumais MC, P, é, choux C, Humbert M, Hinzpeter A, Mercier O, Capuano V, Montani D, Antigny F, Role of KCNK3 Dysfunction in Dasatinib-associated Pulmonary Arterial Hypertension and Endothelial Cell Dysfunction. Am J Respir Cell Mol Biol, 71(1):95-109(2024) [pubmed]

10.1165/rcmb.2023-0185oc;

submitter keyword: apex, channel dysregulation, turboID,KCNK3

Ida Chiara Guerrera
contact affiliation	SFR Necker INSERM US24, Proteomic Platform Necker, France
contact email	chiara.guerrera@inserm.fr
lab head
Chiara guerrera
contact affiliation	Necker proteomics, INSERM
contact email	chiara.guerrera@inserm.fr
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/2025/10/PXD042425

PRIDE project URI

• PRIDE
  1. PXD042425
     1. Label: PRIDE project
     2. Name: KCNK3 channel dysregulation in PAH