Meyer, Magdalena and Jurek, Benjamin and Alfonso-Prieto, Mercedes and Ribeiro, Rui and Milenkovic, Vladimir M. and Winter, Julia and Hoffmann, Petra and Wetzel, Christian H. and Giorgetti, Alejandro and Carloni, Paolo and Neumann, Inga D. (2022) Structure-function relationships of the disease-linked A218T oxytocin receptor variant. MOLECULAR PSYCHIATRY, 27 (2). pp. 907-917. ISSN 1359-4184, 1476-5578
Full text not available from this repository. (Request a copy)Abstract
Various single nucleotide polymorphisms (SNPs) in the oxytocin receptor (OXTR) gene have been associated with behavioral traits, autism spectrum disorder (ASD) and other diseases. The non-synonymous SNP rs4686302 results in the OXTR variant A218T and has been linked to core characteristics of ASD, trait empathy and preterm birth. However, the molecular and intracellular mechanisms underlying those associations are still elusive. Here, we uncovered the molecular and intracellular consequences of this mutation that may affect the psychological or behavioral outcome of oxytocin (OXT)-treatment regimens in clinical studies, and provide a mechanistic explanation for an altered receptor function. We created two monoclonal HEK293 cell lines, stably expressing either the wild-type or A218T OXTR. We detected an increased OXTR protein stability, accompanied by a shift in Ca2+ dynamics and reduced MAPK pathway activation in the A218T cells. Combined whole-genome and RNA sequencing analyses in OXT-treated cells revealed 7823 differentially regulated genes in A218T compared to wild-type cells, including 429 genes being associated with ASD. Furthermore, computational modeling provided a molecular basis for the observed change in OXTR stability suggesting that the OXTR mutation affects downstream events by altering receptor activation and signaling, in agreement with our in vitro results. In summary, our study provides the cellular mechanism that links the OXTR rs4686302 SNP with genetic dysregulations associated with aspects of ASD.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PLASMA OXYTOCIN; BRAIN OXYTOCIN; STRESS; AUTISM; VASOPRESSIN; TRAFFICKING; RELEASE; OXTR; RATS; ACTIVATION; |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Psychiatrie und Psychotherapie Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Dec 2023 10:14 |
| Last Modified: | 12 Dec 2023 10:14 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57005 |
Actions (login required)
 |
View Item |
