A simple mathematical model of cooperativity in receptor mosaics based on the "symmetry rule"

The phenomenon of receptor\u2013receptor interactions was hypothesized about 20 years ago. It has been demonstrated by now that receptor\u2013receptor interactions between G-protein coupled receptors (GPCRs) occur at plasma membrane level and result in the reciprocal modulation of their binding characteristics (i.e., cooperativity). One of the most important feature of this phenomenon is the concept of cluster of receptors, or receptor mosaic (RM). However, no proper mathematical approach has still been available to characterize RMs as far as their receptor composition, receptor topography and order of receptor activation inside the RM. This paper tries to fill the gap. A simple mathematical approach to the cooperativity in RMs formed by dimers of identical receptors and/or by iso-receptors is proposed. To this aim the so-called \u201csymmetry rule\u201d has been considered. This approach allows to describe by means of a simple energy function the effects of receptor composition (number of dimers), spatial organisation (respective location of the dimers) and order of activation (order according to which the single receptors are ligated) on the integrative cooperativity (index) of the RMs

A simple mathematical model of cooperativity in receptor mosaics based on the symmetry rule

The phenomenon of receptor-receptor interactions was hypothesized about 20 years ago. It has been demonstrated by now that receptor-receptor interactions between G-protein coupled receptors (GPCRs) occur at plasma membrane level and result in the reciprocal modulation of their binding characteristics (i.e., cooperativity). One of the most important feature of this phenomenon is the concept of cluster of receptors, or receptor mosaic (RM). However, no proper mathematical approach has still been available to characterize RMs as far as their receptor composition, receptor topography and order of receptor activation inside the RM. This paper tries to fill the gap. A simple mathematical approach to the cooperativity in RMs formed by dimers of identical receptors and/or by iso-receptors is proposed. To this aim the so-called symmetry rule has been considered. This approach allows to describe by means of a simple energy function the effects of receptor composition (number of dimers), spatial organisation (respective location of the dimers) and order of activation (order according to which the single receptors are ligated) on the integrative cooperativity (index) of the RMs

Receptor-receptor interactions, receptor mosaics, and basic principles of molecular network organization - Possible implications for drug development

The phenomenon of receptor-receptor interactions was hypothesized by Agnati and Fuxe in the 1980s, and several indirect proofs were provided in the following years by means of in vitro binding experiments and in vivo experiments in physiological and pathological animal models. This paper aims to outline some of the most important features and consequences of this phenomenon in the frame of the structural and functional aspects of molecular networks. In particular, the concepts of receptor mosaic (RM), and of horizontal and vertical molecular networks (HMNs, VMNs, respectively) are illustrated. To discuss some aspects of the functional organization of molecular networks, not only new data on protein-protein interactions but also the biochemical mechanism of cooperativity will be used. On this basis, some theoretical deductions can be drawn that allow a tentative classification of the RMs and the proposal of the extension of the concept of branching point introduced for enzymes to the possible switching role of some RMs in directing signals to various VMNs. Finally, the cooperativity phenomenon and the so-called symmetry rule will be used to introduce a proper mathematical approach that characterizes RMs as to their receptor composition, receptor topography, and order of receptor activation inside the RM. These new data on G protein\u2013coupled receptors and molecular network organization indicate possible new approaches for drug development

Moonlighting Characteristics of G Protein-coupled Receptors: Focus on Receptor Heteromers and Relevance for Neurodegeneration

It is proposed that the moonlighting concept can be applied to G protein coupled receptors (GPCRs) as, obviously, they can carry out different types of functions. The same motifs in, for example, the third intracellular loop, can moonlight by switching between receptor\u2013receptor interactions and interactions with signaling proteins such as G proteins or calmodulin. A \u2018\u2018guide-and-clasp\u2019\u2019 manner of receptor\u2013receptor interactions has been proposed where the \u2018\u2018adhesive guides\u2019\u2019 may be the triplet homologies. As an example, the triplets AAR (or RAA) and AAE (or EAA) homologies in A2AR-D2R heteromers may guideand- clasp binding not only of the two protomers but also of calmodulin and Gi. A beautiful moonlighting phenomenon in the A2AR-D2R heteromer is that the positively charged D2R N-terminal third intracellular loop epitope (VLRRRRKRVN) may switch between bindings to the negatively charged A2AR epitope (SAQEpSQGNT), localized in the medium segment of the C terminus of the A2A receptor to several negative epitopes of calmodulin. Furthermore, overlapping motifs may favor moonlighting to Gi/o via inter alia electrostatic interaction between triplets AAR(in D2R third intracellular loop) and AAE (Gi/alpha1) (and/or their symmetric variants) contributing to guide-and-clasp D2R-Gi interactions Thus, moonlighting in GPCR heteromers can take place via allosteric receptor\u2013receptor interactions and is also described in D1R-D2R, D2R-5- HT2R,and A1R-P2Y1 heteromers. Allosteric receptor\u2013receptor interactions in GPCR-receptor tyrosine kinases (RTKs) heteromers and postulated ion channel receptor-RTK heteromers-like, for example, AMPA-NMDA-TrkB heteromers may lead to moonlighting of the participating GPCR and RTK protomers altering, for example, the pattern of the five major signaling pathways of the RTKs favoring MAPK and/or mTOR signaling with high relevance for neurodegenerative processes and depression induced atrophy of neurons. Moonlighting may also develop in the intracellular loops and C-terminal of the GPCRs as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptor

Dopamine D2 heteroreceptor complexes and their receptor-receptor interactions in ventral striatum: novel targets for antipsychotic drugs.

This review is focused on the D2 heteroreceptor complexes within the ventral striatum with their receptor-receptor interactions and relevance for the treatment of schizophrenia. A "guide-and-clasp" manner for receptor-receptor interactions is proposed where "adhesive guides" may be amino acid triplet homologies, which were determined for different kinds of D2 heteroreceptor complexes. The first putative D2 heteroreceptor complex to be discovered in relation to schizophrenia was the A2A-D2 heteroreceptor complex where antagonistic A2A-D2 receptor-receptor interactions were demonstrated after A2A agonist treatment in the ventral striatum. The A2A agonist CGS 21680 with atypical antipsychotic properties may at least in part act by increasing β-arrestin2 signaling over the D2 protomer in the A2A-D2 heteroreceptor complex in the ventral striatum. The antagonistic NTS1-D2 interactions in the NTS1-D2 heteroreceptor complex in the ventral striatum are proposed as one molecular mechanism for the potential antipsychotic effects of NT. Indications were obtained that the psychotic actions of the 5-HT2AR hallucinogens LSD and DOI can involve enhancement of D2R protomer signaling via a biased agonist action at the 5-HT2A protomer in the D2-5-HT2A heteroreceptor complex in the ventral striatum. Facilitatory allosteric D2likeR-OTR interactions in heteroreceptor complexes in nucleus accumbens may have a role in social and emotional behaviors. By blocking the D2 protomers of these heteroreceptor complexes, antipsychotics can fail to reduce the negative symptoms of schizophrenia. The discovery of different types of D2 heteroreceptor complexes gives an increased understanding of molecular mechanisms involved in causing schizophrenia and new strategies for its treatment and understanding the side effects of antipsychotics

Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions

Dopamine D(2) and D(4) receptors partially codistribute in the dorsal striatum and appear to play a fundamental role in complex behaviors and motor function. The discovery of D(2)R-D(4.x)R (D(4.2)R, D(4.4)R or D(4.7)R) heteromers has been made in cellular models using coimmunoprecipitation, in situ Proximity Ligation Assays and BRET(1) techniques with the D(2)R and D(4.7)R receptors being the least effective in forming heteromers. Allosteric receptor-receptor interactions in D(2)R-D(4.2)R and D(2)R-D(4.4) R heteromers were observed using the MAPK assays indicating the existence of an enhancing allosteric receptor-receptor interaction in the corresponding heteromers between the two orthosteric binding sites. The bioinformatic predictions suggest the existence of a basic set of common triplets (ALQ and LRA) in the two participating receptors that may contribute to the receptor-receptor interaction interfaces

Fibroblast growth factor receptor 1- 5-hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity.

BACKGROUND: The hippocampus and its 5-hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity. METHODS: The analysis was made with bioluminescence resonance energy transfer, co-immunoprecipitation, in situ proximity ligation assay, binding assay, in cell western and the forced swim test. RESULTS: Using bioluminescence resonance energy transfer analysis, fibroblast growth factor receptor 1 (FGFR1)-5-hydroxytryptamine 1A (5-HT1A) receptor complexes have been demonstrated and their specificity and agonist modulation characterized. Their presence based on co-immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location. In vitro assays on extracellular signal-regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 (FGF2) and a 5-HT1A agonist, and dependent on the heteroreceptor interface. In vitro and in vivo studies also revealed a 5-HT1A agonist induced phosphorylation of FGFR1 and extracellular signal-regulated kinase 1/2 in rat hippocampus without changing FGF2 levels. Co-activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface. The combined acute and repeated intracerebroventricular treatment with FGF2 and 8-OH-DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test. CONCLUSIONS: The findings indicate that neurotrophic and antidepressant effects of 5-HT in brain may, in part, be mediated by activation of the 5-HT1A receptor protomer in the hippocampal FGFR1-5-HT1A receptor complex enhancing the FGFR1 signaling

Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease.

The introduction of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network (GPCR-HetNet) indicated that the allosteric receptor-receptor interactions dramatically increase GPCR diversity and biased recognition and signaling leading to enhanced specificity in signaling. Dysfunction of the GPCR heteroreceptor complexes can lead to brain disease. The findings of serotonin (5-HT) hetero and isoreceptor complexes in the brain over the last decade give new targets for drug development in major depression. Neuromodulation of neuronal networks in depression via 5-HT, galanin peptides and zinc involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer remains a receptor enhancing antidepressant actions through its participation in hetero- and homoreceptor complexes listed above in balance with each other. In depression, neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT and fibroblast growth factor 2 involves either FGFR1-5-HT1A heteroreceptor complexes or the 5-HT isoreceptor complexes such as 5-HT1A-5-HT7 and 5-HT1A-5-HT2A. Neuromodulation of neuronal networks in cocaine use disorder via dopamine (DA) and adenosine signals involve A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and ventral striatum. The excitatory modulation by A2AR agonists of the ventral striato-pallidal GABA anti-reward system via targeting the A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complex holds high promise as a new way to treat cocaine use disorders. Neuromodulation of neuronal networks in schizophrenia via DA, adenosine, glutamate, 5-HT and neurotensin peptides and oxytocin, involving A2AR-D2R, D2R-NMDAR, A2AR-D2R-mGluR5, D2R-5-HT2A and D2R-oxytocinR heteroreceptor complexes opens up a new world of D2R protomer targets in the listed heterocomplexes for treatment of positive, negative and cognitive symptoms of schizophrenia