000165057 001__ 165057
000165057 005__ 20251204150239.0
000165057 0247_ $$2doi$$a10.1021/acs.jmedchem.5c01626
000165057 0248_ $$2sideral$$a146441
000165057 037__ $$aART-2025-146441
000165057 041__ $$aeng
000165057 100__ $$aMuñoz-Reyes, Daniel
000165057 245__ $$aFDA Drug Repurposing Uncovers Modulators of Dopamine D<sub>2</sub> Receptor Localization via Disruption of the NCS-1 Interaction
000165057 260__ $$c2025
000165057 5060_ $$aAccess copy available to the general public$$fUnrestricted
000165057 5203_ $$aDopamine D2 receptor (D2R) regulates key aspects of motor control, cognition, and reward. Its function depends not only on ligand binding and signaling efficacy but also on the dynamic control of receptor localization at the cell surface. Neuronal calcium sensor 1 (NCS-1) interacts with D2R in a Ca2+-dependent manner. Using in vitro and cellular assays, we found that NCS-1 promotes D2R trafficking to the plasma membrane through active exocytosis while preserving canonical receptor pharmacology. A screen of FDA-approved drugs identified protein–protein interaction (PPI) modulators targeting the NCS-1/D2R interface. Azilsartan medoxomil, atorvastatin, and vilazodone disrupt this interaction, reducing D2R surface expression. Structural studies revealed that these compounds target NCS-1, overlap the D2R binding site, and perturb the dynamics of the regulatory helix H10. These findings reveal an unexploited intracellular mechanism to modulate D2R function via PPI modulation, offering a novel strategy to fine-tune dopaminergic tone beyond receptor blockade or direct agonism.
000165057 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PID2019-111737RB-I00$$9info:eu-repo/grantAgreement/ES/AEI/PID2022-137331OB-C31$$9info:eu-repo/grantAgreement/ES/AEI/PID2022-137331OB-C32$$9info:eu-repo/grantAgreement/ES/AEI/PID2022-137331OB-C33$$9info:eu-repo/grantAgreement/ES/CSIC/JAEINT-23-00101$$9info:eu-repo/grantAgreement/ES/MCIU/PID2023-148739NB-I00$$9info:eu-repo/grantAgreement/ES/MICINN-FEDER/PID2020-113359GA-I00
000165057 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000165057 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000165057 700__ $$aAguado, Lorena
000165057 700__ $$0(orcid)0000-0003-3785-298X$$aArroyo-Urea, Sandra$$uUniversidad de Zaragoza
000165057 700__ $$aRequena, Carlos
000165057 700__ $$aPérez-Suárez, Sara
000165057 700__ $$aSánchez-Yepes, Sonia
000165057 700__ $$aArgerich, Josep$$uUniversidad de Zaragoza
000165057 700__ $$aMiró-Rodríguez, Celia
000165057 700__ $$aUlzurrun, Eugenia
000165057 700__ $$aRodríguez-Martín, Eulalia
000165057 700__ $$0(orcid)0000-0002-4254-3148$$aGarcía-Nafría, Javier$$uUniversidad de Zaragoza
000165057 700__ $$aCampillo, Nuria E.
000165057 700__ $$aMansilla, Alicia
000165057 700__ $$aSánchez-Barrena, María José
000165057 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000165057 773__ $$g68, 22 (2025), 23993-24010$$pJ. med. chem.$$tJournal of medicinal chemistry$$x0022-2623
000165057 8564_ $$s9963213$$uhttps://zaguan.unizar.es/record/165057/files/texto_completo.pdf$$yVersión publicada
000165057 8564_ $$s3060678$$uhttps://zaguan.unizar.es/record/165057/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000165057 909CO $$ooai:zaguan.unizar.es:165057$$particulos$$pdriver
000165057 951__ $$a2025-12-04-14:40:11
000165057 980__ $$aARTICLE