Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders: from molecular mechanisms to behavioral regulation.
Final Report Abstract
Results of multiple biochemical, structural and functional studies collected during the last decade clearly indicate that G-protein coupled receptors (GPCRs) exist as oligomeric complexes, which can be critically involved in regulation of receptor trafficking, receptor activation and G- protein coupling. A clinical significance of GPCR oligomerization has also become more evident during recent years, leading to identification of oligomeric complexes as a novel therapeutic target. We have previously shown that serotonin receptors type 7 (5-HT7R) and type 1A (5-HT1AR) can form homodimers, as well as heterodimers4, both in vitro and in vivo. Both 5-HTRs regulate the intracellular level of the second messenger cyclic AMP, although in the opposite direction: the activation of Gs via the 5-HT7R results in increased production of cAMP, while Gi activation via the 5-HT1AR leads to a decrease in cAMP concentration. In our previous studies, we have demonstrated that hetero-dimerization decreases Gi-protein coupling of 5-HT1AR without affecting of the 5-HT7R/Gs signaling. Hetero-dimerization also facilitated internalization of the 5-HT1AR. Within the present proposal, we intended to evaluate the level of 5-HT1AR/5-HT7R hetero-dimerization in different brain regions and to analyze functional consequences of hetero-dimerization, including modulation of intracellular signaling. The second major goal was to elucidate the functional role of 5-HT1AR/5-HT7R hetero-dimerization for the development, maintenance and pathogenesis of depressive disorders. This also implied importance of the 5-HT1AR/5-HT7R hetero-dimers as a potential therapeutic target for the treatment of depression. To achieve these goals, we combined molecular-biological and biochemical techniques with state-of-theart biophysical approaches and quantitative molecular imaging applied at the subcellular, cellular and networks levels. As model systems, we used neuroblastoma cells, primary neuronal cultures as well as acute slices from different brain regions of wild-type and 5-HT7R deficient (5-HT7R KO) mice. To verify whether the depression-like phenotype can modulate 5-HT1AR and 5-HT7R interaction in vivo, we applied chronic unpredictable stress (CUS) rodent models of depression followed by behavioral, biochemical and immunocytochemical analysis.
Publications
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Serotonin receptor oligomerization regulates cAMP-based signaling. Journal of Cell Science, 132(16).
Prasad, Sonal; Ponimaskin, Evgeni & Zeug, Andre
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In Vitro Development of Human iPSC-Derived Functional Neuronal Networks on Laser-Fabricated 3D Scaffolds. ACS Applied Materials & Interfaces, 13(7), 7839-7853.
Koroleva, Anastasia; Deiwick, Andrea; El-Tamer, Ayman; Koch, Lothar; Shi, Yichen; Estévez-Priego, Estefanía; Ludl, Adriaan-Alexander; Soriano, Jordi; Guseva, Daria; Ponimaskin, Evgeni & Chichkov, Boris
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Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder. ACS Chemical Neuroscience, 12(8), 1313-1327.
Lacivita, Enza; Niso, Mauro; Mastromarino, Margherita; Garcia, Silva Andrea; Resch, Cibell; Zeug, Andre; Loza, María I.; Castro, Marián; Ponimaskin, Evgeni & Leopoldo, Marcello
