PXD052839

PXD052839 is an original dataset announced via ProteomeXchange.

Title	The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1 S409A knock-in mice via PKA-dependent and independent mechanisms
Description	We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABAA 3 subunits partially blocked apremilast-mediated decreases in alcohol drinking. Here, we produced Gabrb1-S409A knock-in mice to render GABAA β1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in 1 subunit expression or phosphorylation at other residues. 1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits in the hippocampus or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type mice but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 completely prevented apremilast modulation of ataxia induced by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting either PKA or EPAC2 (an exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute functional tolerance to ethanol ataxia and increased acute sensitivity to ethanol in both genotypes. However, there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of β1-containing GABAA receptors is not required for apremilast’s effects on acute tolerance to ethanol or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we also identified EPAC2 as an additional cAMP-dependent signaling mechanism by which apremilast regulates responses to GABAergic drugs.
HostingRepository	PRIDE
AnnounceDate	2025-10-06
AnnouncementXML	Submission_2025-10-05_16:05:38.759.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD052839
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Joshua Smalley
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-04 18:19:01	ID requested
⏵ 1	2025-10-05 16:05:39	announced

10.1016/j.neuropharm.2024.110035;

10.6019/PXD052839;

Blednov YA, Shawlot W, Homanics GE, Osterndorff-Kahanek EA, Mason S, Mayfield J, Smalley JL, Moss SJ, Messing RO, The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1-S409A knock-in mice via PKA-dependent and independent mechanisms. Neuropharmacology, 257():110035(2024) [pubmed]

submitter keyword: GABA A Receptor, Mutany, Apremilast, PKA, GABRB1, Ethanol

Joshua Smalley
contact affiliation	Tufts University
contact email	joshua.smalley@tufts.edu
lab head
Joshua Smalley
contact affiliation	Tufts University
contact email	joshua.smalley@tufts.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/2025/10/PXD052839

PRIDE project URI

• PRIDE
  1. PXD052839
     1. Label: PRIDE project
     2. Name: The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1 S409A knock-in mice via PKA-dependent and independent mechanisms