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Table 1. Examples of treatment strategies related to GPCR heteroreceptor complexes.

Table 1 Examples of treatment strategies related to GPCR heteroreceptor complexes.

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Figure 1. 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).
Figure 1. 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).
rigure 2. ranorama of serotonin homo and heteroreceptor complexes of relevance tor Major Ve- pressive 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.
rigure 2. ranorama of serotonin homo and heteroreceptor complexes of relevance tor Major Ve- pressive 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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