Review
doi: 10.3390/cells11111826.Dysfunctional Heteroreceptor Complexes as Novel Targets for the Treatment of Major Depressive and Anxiety Disorders
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- PMID:35681521
- PMCID: PMC9180493
- DOI: 10.3390/cells11111826
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Review
Dysfunctional Heteroreceptor Complexes as Novel Targets for the Treatment of Major Depressive and Anxiety Disorders
Miguel Pérez de la Mora et al. Cells..
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Abstract
Among mental diseases, major depressive disorder (MDD) and anxiety deserve a special place due to their high prevalence and their negative impact both on society and patients suffering from these disorders. Consequently, the development of novel strategies designed to treat them quickly and efficiently, without or at least having limited side effects, is considered a highly important goal. Growing evidence indicates that emerging properties are developed on recognition, trafficking, and signaling of G-protein coupled receptors (GPCRs) upon their heteromerization with other types of GPCRs, receptor tyrosine kinases, and ionotropic receptors such as N-methyl-D-aspartate (NMDA) receptors. Therefore, to develop new treatments for MDD and anxiety, it will be important to identify the most vulnerable heteroreceptor complexes involved in MDD and anxiety. This review focuses on how GPCRs, especially serotonin, dopamine, galanin, and opioid heteroreceptor complexes, modulate synaptic and volume transmission in the limbic networks of the brain. We attempt to provide information showing how these emerging concepts can contribute to finding new ways to treat both MDD and anxiety disorders.
Keywords: G-protein coupled receptors; anxiety; depression; heteromeric complexes; receptor oligomerization; receptor-receptor interactions.
Conflict of interest statement
The authors have no affiliations or financial involvement with any organization or entity having financial interest or conflict with the subject matter or the material discussed in the manuscript.
Figures
Several biophysical (BRET, FRET) and biochemical (radioligand binding assay, in situ Proximity Ligation Assay (in situ PLA), Gene Reporter Assay, Co-immunoprecipitation (CO-IP), and internalization assays (Path-hunter arrestin)) methods have made possible the understanding of the molecular mechanisms involved in the integration of the receptor-receptor interactions in the plasma membrane. Herein (central panel), the example of the dopamine (D2R) and Oxytocin (OXTR) homo and heteroreceptor complexes and their balance. (A) Illustration of the in situ PLA analysis of the D2R-OXTR heteroreceptor complexes (red blub/clusters) in the nucleus accumbens of the rat brain. (B) Gene reporter assays (CREB, SRE, NFAT, etc.) and internalization assays (B-arrestin Path-hunter assay, etc.) made possible the understanding of the panorama of the signal integration and transcriptional machinery after the activation of the various homo and heteroreceptor complexes in the plasma membrane. (C) The developments of heterobivalent and small interface peptides made it possible to study the receptor-receptor interface of these complexes. (D) Illustration of the analysis of the formation of D2R-OXTR heteroreceptor complexes using Bioluminescence resonance energy transfer method (BRET2).
Panorama of serotonin homo and heteroreceptor complexes of relevance for Major Depressive Disorders (MDD) with a location in the plasma membrane. Recent work has strongly indicated the impact of 5-HT1AR-5-HT2AR isoreceptor complexes and the 5-HT1AR-FGFR1, 5-HT1AR-GalR1-GalR2 heteroreceptor complexes and their balance between each other in MDD. The significant molecular mechanism is represented by allosteric receptor-receptor interactions within the heteroreceptor complexes. Inhibitory and enhancing allosteric receptor-receptor interactions develop in the 5-HT1AR-5HT2AR and 5-HT1AR-FGFR1 heteroreceptor complexes, respectively. In the trimeric 5-HT1AR-GalR1-GalR2 heteroreceptor complexes, a cascade of inhibitory interactions takes place. The 5-HT1AR protomer produced a negative allosteric modulation of the GalR1 protomer, inducing a removal of the inhibitory allosteric interactions between the GalR1 and GalR2 protomers (indicated as red dashed lines), leading to antidepressant events. Another molecular mechanism of strong interest is the potential disbalance that may develop between the various types of homo and heteroreceptor complexes. These molecular mechanisms involve both changes in receptor protomers recognition, signaling (including the panorama of interacting proteins and the intracellular cascades), and internalization. These events take place in key neuronal pathways of the limbic system, having an important role in emotional events.
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This work was supported by the grant IN206820 (M.P.d.l.M) from Dirección General de Asuntos del Personal Académico (DGAPA). In addition, the grant FIS/IMSS/PROT/G14/1320 ET-C and that from: Stiftelsen Olle Engkvist Byggmästare, Stockholm, Sweden, Swedish Medical Research Council. Also supported by project EMERGIA 2020-39318 founded by Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020) to D.O.B-E.