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The role of adenosine A2A receptor (A2AR) and striatal-enriched protein tyrosine phosphatase (STEP) interactions in the striatal-pallidal GABA neurons was recently discussed in relation to A2AR overexpression and cocaine-induced increases of brain adenosine levels. As to phosphorylation, combined activation of A2AR and metabotropic glutamate receptor 5 (mGluR5) in the striatal-pallidal GABA neurons appears necessary for phosphorylation of the GluA1 unit of the AMPA receptor to take place. Robert Yasuda (J Neurochem 152: 270–272, 2020) focused on finding a general mechanism by which STEP activation is enhanced by increased A2AR transmission in striatal-pallidal GABA neurons expressing A2AR and dopamine D2 receptor. In his Editorial, he summarized in a clear way the significant effects of A2AR activation on STEP in the dorsal striatal-pallidal GABA neurons which involves a rise of intracellular levels of calcium causing STEP activation through its dephosphorylation. However, the presence of the A2AR in an A2AR-fibroblast growth factor receptor 1 (FGFR1) heteroreceptor complex can be required in the dorsal striatal-pallidal GABA neurons for the STEP activation. Furthermore, Won et al. (Proc Natl Acad Sci USA 116: 8028–8037, 2019) found in mass spectrometry experiments that the STEP splice variant STEP61 can bind to mGluR5 and inactivate it. In addition, A2AR overexpression can lead to increased formation of A2AR-mGluR5 heterocomplexes in ventral striatal-pallidal GABA neurons. It involves enhanced facilitatory allosteric interactions leading to increased Gq-mediated mGluR5 signaling activating STEP. The involvement of both A2AR and STEP in the actions of cocaine on synaptic downregulation was also demonstrated. The enhancement of mGluR5 protomer activity by the A2AR protomer in A2AR-mGluR5 heterocomplexes in the nucleus accumbens shell appears to have a novel significant role in STEP mechanisms by both enhancing the activation of STEP and being a target for STEP61.
Dasiel O. Borroto-Escuela; Luca Ferraro; Sarah Beggiato; Manuel Narváez; Ramon Fores-Pons; Jose E. Alvarez-Contino; Karolina Wydra; Małgorzata Frankowska; Michael Bader; Małgorzata Filip; Kjell Fuxe. The coming together of allosteric and phosphorylation mechanisms in the molecular integration of A2A heteroreceptor complexes in the dorsal and ventral striatal-pallidal GABA neurons. Pharmacological Reports 2021, 1 -13.
AMA StyleDasiel O. Borroto-Escuela, Luca Ferraro, Sarah Beggiato, Manuel Narváez, Ramon Fores-Pons, Jose E. Alvarez-Contino, Karolina Wydra, Małgorzata Frankowska, Michael Bader, Małgorzata Filip, Kjell Fuxe. The coming together of allosteric and phosphorylation mechanisms in the molecular integration of A2A heteroreceptor complexes in the dorsal and ventral striatal-pallidal GABA neurons. Pharmacological Reports. 2021; ():1-13.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Luca Ferraro; Sarah Beggiato; Manuel Narváez; Ramon Fores-Pons; Jose E. Alvarez-Contino; Karolina Wydra; Małgorzata Frankowska; Michael Bader; Małgorzata Filip; Kjell Fuxe. 2021. "The coming together of allosteric and phosphorylation mechanisms in the molecular integration of A2A heteroreceptor complexes in the dorsal and ventral striatal-pallidal GABA neurons." Pharmacological Reports , no. : 1-13.
The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.
Dasiel Borroto-Escuela; Patrizia Ambrogini; Manuel Narvaez; Valentina Di Liberto; Sarah Beggiato; Luca Ferraro; Ramon Fores-Pons; Jose Alvarez-Contino; Alexander Lopez-Salas; Giuseppa Mudò; Zaida Díaz-Cabiale; Kjell Fuxe. Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases. Cells 2021, 10, 1902 .
AMA StyleDasiel Borroto-Escuela, Patrizia Ambrogini, Manuel Narvaez, Valentina Di Liberto, Sarah Beggiato, Luca Ferraro, Ramon Fores-Pons, Jose Alvarez-Contino, Alexander Lopez-Salas, Giuseppa Mudò, Zaida Díaz-Cabiale, Kjell Fuxe. Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases. Cells. 2021; 10 (8):1902.
Chicago/Turabian StyleDasiel Borroto-Escuela; Patrizia Ambrogini; Manuel Narvaez; Valentina Di Liberto; Sarah Beggiato; Luca Ferraro; Ramon Fores-Pons; Jose Alvarez-Contino; Alexander Lopez-Salas; Giuseppa Mudò; Zaida Díaz-Cabiale; Kjell Fuxe. 2021. "Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases." Cells 10, no. 8: 1902.
The study of the affective dimension of transversal competences is essential for the development of responsible behaviors and maintaining attitudes committed to sustainable development. The importance attributed to each of these factors can predict behavior implementation and awareness of values for sustainable development that reflect the acquisition and internalization of sustainability-related generic competences. This study aimed to determine the psychometric properties of the affective dimension of the Generic Macro-Competence Assessment (AGMA) scale by applying Rasch measurement model to a sample of Spanish university students, comprising 387 Spanish university students (74.9% women; mean age = 21.24; WD = 3.54; range: 17–34). Results demonstrated a lack of adjustment to the Rasch model due to item 1, and all items showed disordered response category thresholds. The remaining nine-item scale achieved all requirements of the model (χ2 = 61.46; p = 0.052), including unidimensionality. Thus, the scale’s psychometric properties indicate an easy-to-apply instrument for screening these factors for coping strategies in undergraduate and graduate Spanish students. The results can help in justifying the design of interdisciplinary intervention programs, in which affective factors are essential for sustainable development education.
Francisco Morales-Rodríguez; Manuel Martí-Vilar; Manuel Peláez; José Lozano; Juan Martínez-Ramón; Alfonso Caracuel. Psychometric Properties of the Affective Dimension of the Generic Macro-Competence Assessment Scale: Analysis Using Rasch Model. Sustainability 2021, 13, 6904 .
AMA StyleFrancisco Morales-Rodríguez, Manuel Martí-Vilar, Manuel Peláez, José Lozano, Juan Martínez-Ramón, Alfonso Caracuel. Psychometric Properties of the Affective Dimension of the Generic Macro-Competence Assessment Scale: Analysis Using Rasch Model. Sustainability. 2021; 13 (12):6904.
Chicago/Turabian StyleFrancisco Morales-Rodríguez; Manuel Martí-Vilar; Manuel Peláez; José Lozano; Juan Martínez-Ramón; Alfonso Caracuel. 2021. "Psychometric Properties of the Affective Dimension of the Generic Macro-Competence Assessment Scale: Analysis Using Rasch Model." Sustainability 13, no. 12: 6904.
A need for new antidepressants is necessary since traditional antidepressants have several flaws. Neuropeptide Y(NPY) Y1 receptor (NPYY1R) and galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the hippocampus. The current study assesses the antidepressant effects induced by GALR2 and NPYY1R coactivation, together with the evaluation of cell proliferation through 5‐Bromo‐2'‐deoxyuridine expression within the dentate gyrus of the ventral hippocampus (vDG). We employed in situ proximity ligation assay to manifest GALR2/NPYY1R heteroreceptor complexes. Additionally, the expression pattern of GALR2 and the activation of the extracellular‐regulated kinases (ERK) pathway after GALR2 and NPYY1R costimulation in cell cultures were examined. GALR2 and NPYY1R coactivation resulted in sustained antidepressant behaviors in the FST after 24 h, linked to increased cell proliferation in the vDG. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was observed in vDG, on doublecortin‐expressing neuroblasts. Recruitment of the GALR2 expression to the plasma membrane was observed upon the coactivation of GALR2 and NPYY1R in cell cultures, presumably associated to the enhanced effects on the activation of ERK pathway. GALR2 may promote the GALR2/NPYY1R heteroreceptor complexes formation in the ventral hippocampus. It may induce a transformation of cell proliferation toward a neuronal lineage by enhancement of ERK pathway. Thus, it may give the mechanism for the antidepressant behavior observed. These results may provide the basis for the development of heterobivalent agonist pharmacophores, targeting GALR2/NPYY1R heteromers, especially in the neuronal precursor cells of the dentate gyrus in the ventral hippocampus for the novel treatment of depression.
Dasiel O. Borroto‐Escuela; Mariana Pita‐Rodriguez; Ramón Fores‐Pons; Miguel A. Barbancho Md; Kjell Fuxe; Manuel Narváez Md. Galanin and neuropeptide Y interactions elicit antidepressant activity linked to neuronal precursor cells of the dentate gyrus in the ventral hippocampus. Journal of Cellular Physiology 2020, 236, 3565 -3578.
AMA StyleDasiel O. Borroto‐Escuela, Mariana Pita‐Rodriguez, Ramón Fores‐Pons, Miguel A. Barbancho Md, Kjell Fuxe, Manuel Narváez Md. Galanin and neuropeptide Y interactions elicit antidepressant activity linked to neuronal precursor cells of the dentate gyrus in the ventral hippocampus. Journal of Cellular Physiology. 2020; 236 (5):3565-3578.
Chicago/Turabian StyleDasiel O. Borroto‐Escuela; Mariana Pita‐Rodriguez; Ramón Fores‐Pons; Miguel A. Barbancho Md; Kjell Fuxe; Manuel Narváez Md. 2020. "Galanin and neuropeptide Y interactions elicit antidepressant activity linked to neuronal precursor cells of the dentate gyrus in the ventral hippocampus." Journal of Cellular Physiology 236, no. 5: 3565-3578.
Adenosine A2A receptors (A2AR) are crucial in facilitating the BDNF action on synaptic transmission in the rat hippocampus primarily upon ageing. Furthermore, it has been suggested that A2AR-Tropomyosin related kinase B receptor (TrkB) crosstalk has a pivotal role in adenosine A2AR-mediated modulation of the BDNF action on hippocampal plasticity. Considering the impact of the above receptors interplay on what concerns BDNF-induced enhancement of synaptic transmission, gaining a better insight into the mechanisms behind this powerful crosstalk becomes of primary interest. Using in situ proximity ligation assay (PLA), the existence of a direct physical interaction between adenosine A2AR and TrkB is demonstrated. The A2AR-TrkB heteroreceptor complexes show a heterogeneous distribution within the rat dorsal hippocampus. High densities of the heteroreceptor complexes were observed in the pyramidal cell layers of CA1-CA3 regions and in the polymorphic layer of the dentate gyrus (DG). The stratum radiatum of the CA1-3 regions showed positive PLA signal in contrast to the oriens region. The molecular and granular layers of the DG also lacked significant densities of PLA positive heteroreceptor complexes, but subgranular zone showed some PLA positive cells. Their allosteric receptor-receptor interactions may significantly modulate BDNF signaling impacting on hippocampal plasticity which is impaired upon ageing.
Michael Di Palma; Stefano Sartini; Davide Lattanzi; Riccardo Cuppini; Mariana Pita-Rodriguez; Yoslandy Diaz-Carmenate; Manuel Narvaez; Kjell Fuxe; Dasiel O. Borroto-Escuela; Patrizia Ambrogini. Evidence for the existence of A2AR-TrkB heteroreceptor complexes in the dorsal hippocampus of the rat brain: Potential implications of A2AR and TrkB interplay upon ageing. Mechanisms of Ageing and Development 2020, 190, 111289 .
AMA StyleMichael Di Palma, Stefano Sartini, Davide Lattanzi, Riccardo Cuppini, Mariana Pita-Rodriguez, Yoslandy Diaz-Carmenate, Manuel Narvaez, Kjell Fuxe, Dasiel O. Borroto-Escuela, Patrizia Ambrogini. Evidence for the existence of A2AR-TrkB heteroreceptor complexes in the dorsal hippocampus of the rat brain: Potential implications of A2AR and TrkB interplay upon ageing. Mechanisms of Ageing and Development. 2020; 190 ():111289.
Chicago/Turabian StyleMichael Di Palma; Stefano Sartini; Davide Lattanzi; Riccardo Cuppini; Mariana Pita-Rodriguez; Yoslandy Diaz-Carmenate; Manuel Narvaez; Kjell Fuxe; Dasiel O. Borroto-Escuela; Patrizia Ambrogini. 2020. "Evidence for the existence of A2AR-TrkB heteroreceptor complexes in the dorsal hippocampus of the rat brain: Potential implications of A2AR and TrkB interplay upon ageing." Mechanisms of Ageing and Development 190, no. : 111289.
In the 1980s and 1990s, the concept was introduced that molecular integration in the Central Nervous System could develop through allosteric receptor–receptor interactions in heteroreceptor complexes presents in neurons. A number of adenosine–dopamine heteroreceptor complexes were identified that lead to the A2A-D2 heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A2A-D2 receptor–receptor interactions and their presence in the ventral striato-pallidal GABA anti-reward neurons leading to reduction of positive symptoms. Other types of adenosine A2A heteroreceptor complexes are also discussed in relation to this disease, such as A2A-D3 and A2A-D4 heteroreceptor complexes as well as higher order A2A-D2-mGluR5 and A2A-D2-Sigma1R heteroreceptor complexes. The A2A receptor protomer can likely modulate the function of the D4 receptors of relevance for understanding cognitive dysfunction in schizophrenia. A2A-D2-mGluR5 complex is of interest since upon A2A/mGluR5 coactivation they appear to synergize in producing strong inhibition of the D2 receptor protomer. For understanding the future of the schizophrenia treatment, the vulnerability of the current A2A-D2like receptor complexes will be tested in animal models of schizophrenia. A2A-D2-Simag1R complexes hold the highest promise through Sigma1R enhancement of inhibition of D2R function. In line with this work, Lara proposed a highly relevant role of adenosine for neurobiology of schizophrenia.
Dasiel O. Borroto-Escuela; Luca Ferraro; Manuel Narvaez; Sergio Tanganelli; Sarah Beggiato; Fang Liu; Alicia Rivera; Kjell Fuxe. Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia. Cells 2020, 9, 1077 .
AMA StyleDasiel O. Borroto-Escuela, Luca Ferraro, Manuel Narvaez, Sergio Tanganelli, Sarah Beggiato, Fang Liu, Alicia Rivera, Kjell Fuxe. Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia. Cells. 2020; 9 (5):1077.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Luca Ferraro; Manuel Narvaez; Sergio Tanganelli; Sarah Beggiato; Fang Liu; Alicia Rivera; Kjell Fuxe. 2020. "Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia." Cells 9, no. 5: 1077.
The majority of the fibroblast growth factor receptor 1-serotonin 1 A receptor (FGFR1-5-HT1AR) heterocomplexes in the hippocampus appeared to be located mainly in the neuronal networks and a relevant target for antidepressant drugs. Through a neurochemical and electrophysiological analysis it was therefore tested in the current study if astrocytic FGFR1-5-HT1AR heterocomplexes also exist in hippocampus. They may modulate the structure and function of astroglia in the hippocampus leading to possible changes in the gamma oscillations. Localization of hippocampal FGFR1-5-HT1AR heterocomplexes in astrocytes was found using in situ proximity ligation assay combined with immunohistochemistry using glial fibrillary acidic protein (GFAP) immunoreactivity as a marker for astroglia. Acute i.c.v. treatment with 8-OH-DPAT alone or together with basic fibroblast growth factor (FGF2) significantly increased FGFR1-5-HT1AR heterocomplexes in the GFAP positive cells, especially in the polymorphic layer of the dentate gyrus (PoDG) but also in the CA3 area upon combined treatment. No other hippocampal regions were studied. Also, structural plasticity changes were observed in the astrocytes, especially in the PoDG region, upon these pharmacological treatments. They may also be of relevance for enhancing the astroglial volume transmission with increased modulation of the neuronal networks in the regions studied. The effects of combined FGF2 and 5-HT agonist treatments on gamma oscillations point to a significant antagonistic interaction in astroglial FGFR1-5-HT1AR heterocomplexes that may contribute to counteraction of the 5-HT1AR-mediated decrease of gamma oscillations. This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.
Manuel Narváez; Yuniesky Andrade-Talavera; Ismael Valladolid-Acebes; Magnus Fredriksson; Pia Siegele; Alejandro Hernandez-Sosa; André Fisahn; Kjell Fuxe; Dasiel O. Borroto-Escuela. Existence of FGFR1-5-HT1AR heteroreceptor complexes in hippocampal astrocytes. Putative link to 5-HT and FGF2 modulation of hippocampal gamma oscillations. Neuropharmacology 2020, 170, 108070 .
AMA StyleManuel Narváez, Yuniesky Andrade-Talavera, Ismael Valladolid-Acebes, Magnus Fredriksson, Pia Siegele, Alejandro Hernandez-Sosa, André Fisahn, Kjell Fuxe, Dasiel O. Borroto-Escuela. Existence of FGFR1-5-HT1AR heteroreceptor complexes in hippocampal astrocytes. Putative link to 5-HT and FGF2 modulation of hippocampal gamma oscillations. Neuropharmacology. 2020; 170 ():108070.
Chicago/Turabian StyleManuel Narváez; Yuniesky Andrade-Talavera; Ismael Valladolid-Acebes; Magnus Fredriksson; Pia Siegele; Alejandro Hernandez-Sosa; André Fisahn; Kjell Fuxe; Dasiel O. Borroto-Escuela. 2020. "Existence of FGFR1-5-HT1AR heteroreceptor complexes in hippocampal astrocytes. Putative link to 5-HT and FGF2 modulation of hippocampal gamma oscillations." Neuropharmacology 170, no. : 108070.
The current study was performed to establish the actions of nanomolar concentrations of cocaine, not blocking the dopamine transporter, on dopamine D2 receptor (D2R)-sigma 1 receptor (δ1R) heteroreceptor complexes and the D2R protomer recognition, signaling and internalization in cellular models. We report the existence of D2R-δ1R heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum, with different distribution patterns using the in situ proximity ligation assay. Also, through BRET, these heteromers were demonstrated in HEK293 cells. Furthermore, saturation binding assay demonstrated that in membrane preparations of HEK293 cells coexpressing D2R and δ1R, cocaine (1 nM) significantly increased the D2R Bmax values over cells singly expressing D2R. CREB reporter luc-gene assay indicated that coexpressed δ1R significantly reduced the potency of the D2R-like agonist quinpirole to inhibit via D2R activation the forskolin induced increase of the CREB signal. In contrast, the addition of 100 nM cocaine was found to markedly increase the quinpirole potency to inhibit the forskolin-induced increase of the CREB signal in the D2R-δ1R cells. These events were associated with a marked reduction of cocaine-induced internalization of D2R protomers in D2R-δ1R heteromer-containing cells vs D2R singly expressing cells as studied by means of confocal analysis of D2R-δ1R trafficking and internalization. Overall, the formation of D2R-δ1R heteromers enhanced the ability of cocaine to increase the D2R protomer function associated with a marked reduction of its internalization. The existence of D2R-δ1R heteromers opens up a new understanding of the acute actions of cocaine.
Dasiel O. Borroto-Escuela; Manuel Narváez; Wilber Romero-Fernández; Luca Pinton; Karolina Wydra; Malgorzata Filip; Sarah Beggiato; Sergio Tanganelli; Luca Ferraro; Kjell Fuxe. Acute Cocaine Enhances Dopamine D2R Recognition and Signaling and Counteracts D2R Internalization in Sigma1R-D2R Heteroreceptor Complexes. Molecular Neurobiology 2019, 56, 7045 -7055.
AMA StyleDasiel O. Borroto-Escuela, Manuel Narváez, Wilber Romero-Fernández, Luca Pinton, Karolina Wydra, Malgorzata Filip, Sarah Beggiato, Sergio Tanganelli, Luca Ferraro, Kjell Fuxe. Acute Cocaine Enhances Dopamine D2R Recognition and Signaling and Counteracts D2R Internalization in Sigma1R-D2R Heteroreceptor Complexes. Molecular Neurobiology. 2019; 56 (10):7045-7055.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Manuel Narváez; Wilber Romero-Fernández; Luca Pinton; Karolina Wydra; Malgorzata Filip; Sarah Beggiato; Sergio Tanganelli; Luca Ferraro; Kjell Fuxe. 2019. "Acute Cocaine Enhances Dopamine D2R Recognition and Signaling and Counteracts D2R Internalization in Sigma1R-D2R Heteroreceptor Complexes." Molecular Neurobiology 56, no. 10: 7045-7055.
G protein-coupled receptors (GPCRs) complexes and their allosteric receptor–receptor interactions represent a new fundamental principle in molecular medicine for integration of transmitter signals in the plasma membrane. The allosteric receptor–receptor interactions in heteroreceptor complexes give diversity, specificity, and bias to the receptor protomers due to conformational changes in discrete domains leading to changes in receptor protomer function and their pharmacology. Therefore, a novel understanding of the molecular basis of central nervous system diseases should consider this phenomena and new strategies for mental and neurodegenerative disorders treatment should target heteroreceptor complexes based on a new pharmacology with combined treatment, multi-targeted drugs and heterobivalent drugs. In this chapter, it is described a technique to visualize the majority of G protein-coupled receptor allosteric receptor–receptor interactions in sections of frozen brain tissue using receptor autoradiography. The basic procedure involves incubating slide-mounted tissue sections with radioligands, washing and drying of the sections with specifically bound ligands under conditions that preserve ligand binding, and visualizing and quantifying the binding sites in the tissues. Protocols for brain extraction and sectioning, radioligand exposure, autoradiogram generation, and data quantification are provided, as are the optimal incubation conditions for the autoradiographic visualization of allosteric receptor–receptor interactions using agonist and antagonist radioligands.
Manuel Narvaez; Fidel Corrales; Ismel Brito; Ismael Valladolid-Acebes; Kjell Fuxe; Dasiel O. Borroto-Escuela. Analysis and Quantification of GPCR Heteroreceptor Complexes and Their Allosteric Receptor–Receptor Interactions Using Radioligand Binding Autoradiography. Animal Models of Drug Addiction 2018, 15 -23.
AMA StyleManuel Narvaez, Fidel Corrales, Ismel Brito, Ismael Valladolid-Acebes, Kjell Fuxe, Dasiel O. Borroto-Escuela. Analysis and Quantification of GPCR Heteroreceptor Complexes and Their Allosteric Receptor–Receptor Interactions Using Radioligand Binding Autoradiography. Animal Models of Drug Addiction. 2018; ():15-23.
Chicago/Turabian StyleManuel Narvaez; Fidel Corrales; Ismel Brito; Ismael Valladolid-Acebes; Kjell Fuxe; Dasiel O. Borroto-Escuela. 2018. "Analysis and Quantification of GPCR Heteroreceptor Complexes and Their Allosteric Receptor–Receptor Interactions Using Radioligand Binding Autoradiography." Animal Models of Drug Addiction , no. : 15-23.
Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term “heteroreceptor complexes” was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A–FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A–FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A–5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1–15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1–GalR2–5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.
Dasiel O. Borroto-Escuela; Manuel Narvaez; Patrizia Ambrogini; Luca Ferraro; Ismel Brito; Wilber Romero-Fernandez; Yuniesky Andrade-Talavera; Antonio Flores-Burgess; Carmelo Millón; Belen Gago; Jose A. Narvaez; Yuji Odagaki; Miklos Palkovits; Zaida Díaz-Cabiale; Kjell Fuxe. Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment. Molecules 2018, 23, 1341 .
AMA StyleDasiel O. Borroto-Escuela, Manuel Narvaez, Patrizia Ambrogini, Luca Ferraro, Ismel Brito, Wilber Romero-Fernandez, Yuniesky Andrade-Talavera, Antonio Flores-Burgess, Carmelo Millón, Belen Gago, Jose A. Narvaez, Yuji Odagaki, Miklos Palkovits, Zaida Díaz-Cabiale, Kjell Fuxe. Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment. Molecules. 2018; 23 (6):1341.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Manuel Narvaez; Patrizia Ambrogini; Luca Ferraro; Ismel Brito; Wilber Romero-Fernandez; Yuniesky Andrade-Talavera; Antonio Flores-Burgess; Carmelo Millón; Belen Gago; Jose A. Narvaez; Yuji Odagaki; Miklos Palkovits; Zaida Díaz-Cabiale; Kjell Fuxe. 2018. "Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment." Molecules 23, no. 6: 1341.
Adenosine 2A receptor (A2AR) agonists were indicated to reduce cocaine reward and cocaine seeking mainly through activation of antagonistic allosteric A2AR-dopamine D2R (D2R) interactions in A2AR-D2R heteroreceptor complexes. Furthermore, it was shown that modulation of cocaine reward involves antagonistic A2AR-D2R interactions in the ventral but not the dorsal striatum in rats. In the current work the proximity ligation assay (PLA) was used to further study the A2AR-D2R heteroreceptor complexes in the nucleus accumbens shell and core as well as the dorsal striatum under the influence of cocaine self-administration in rats. A significant increase in the A2AR-D2R PLA positive clusters was observed in the nucleus accumbens shell but not in the other regions vs yoked saline controls using the duolink software. Additionally, cocaine self-administration evoked a selective and significant increase in the density of D2R-sigma1R positive clusters in the nucleus accumbens shell vs yoked saline controls, while a significant reduction of the density of the D2R-sigma1R positive clusters was found in the dorsal part of the dorsal striatum. The results suggest that cocaine self-administration can reorganize A2AR and D2R into increased A2AR-D2R heteroreceptor complexes in the nucleus accumbens shell associated with increases in the D2R-sigma1R heteroreceptor complexes in this region. This reorganization can contribute to the demonstrated anti-cocaine actions of A2A receptor agonists and the putative formation of A2AR-D2R-sigma1R heterocomplexes.
Dasiel O. Borroto-Escuela; Manuel Narváez; Karolina Wydra; Julia Pintsuk; Luca Pinton; Antonio Jimenez-Beristain; Michael Di Palma; Joanna Jastrzębska; Malgorzata Filip; Kjell Fuxe. Cocaine self-administration specifically increases A2AR-D2R and D2R-sigma1R heteroreceptor complexes in the rat nucleus accumbens shell. Relevance for cocaine use disorder. Pharmacology Biochemistry and Behavior 2017, 155, 24 -31.
AMA StyleDasiel O. Borroto-Escuela, Manuel Narváez, Karolina Wydra, Julia Pintsuk, Luca Pinton, Antonio Jimenez-Beristain, Michael Di Palma, Joanna Jastrzębska, Malgorzata Filip, Kjell Fuxe. Cocaine self-administration specifically increases A2AR-D2R and D2R-sigma1R heteroreceptor complexes in the rat nucleus accumbens shell. Relevance for cocaine use disorder. Pharmacology Biochemistry and Behavior. 2017; 155 ():24-31.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Manuel Narváez; Karolina Wydra; Julia Pintsuk; Luca Pinton; Antonio Jimenez-Beristain; Michael Di Palma; Joanna Jastrzębska; Malgorzata Filip; Kjell Fuxe. 2017. "Cocaine self-administration specifically increases A2AR-D2R and D2R-sigma1R heteroreceptor complexes in the rat nucleus accumbens shell. Relevance for cocaine use disorder." Pharmacology Biochemistry and Behavior 155, no. : 24-31.
New findings show existence of FGFR1-5-HT1A heteroreceptor complexes in 5-HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus. Synergistic receptor–receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity. The existence of FGFR1-5-HT1A heteroreceptor complexes also in midbrain raphe 5-HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5-HT levels can cause an activation of the FGF-2/FGFR1 mechanism in these nerve cells as well. Therefore, the agonist modulation of the FGFR1-5-HT1A heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5-HT nerve cells. The combined i.c.v. treatment with FGF-2 and the 5-HT1A agonist 8-OHDPAT synergistically increased FGFR1 and ERK1/2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells. Cotreatment with FGF2 and the 5-HT1A agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5-HT immunoreactivity. These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the 5-HT1A receptor. Taken together, the 5-HT1A autoreceptors by being part of a FGFR1-5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells appears to have also a trophic role in the central 5-HT neuron systems besides playing a key role in reducing the firing of these neurons.
Dasiel O. Borroto-Escuela; Mileidys Pérez-Alea; Manuel Narvaez; Alexander O. Tarakanov; Giuseppa Mudo'; Antonio Jiménez-Beristain; Luigi F. Agnati; Francisco Ciruela; Natale Belluardo; Kjell Fuxe. Enhancement of the FGFR1 signaling in the FGFR1-5-HT1A heteroreceptor complex in midbrain raphe 5-HT neuron systems. Relevance for neuroplasticity and depression. Biochemical and Biophysical Research Communications 2015, 463, 180 -186.
AMA StyleDasiel O. Borroto-Escuela, Mileidys Pérez-Alea, Manuel Narvaez, Alexander O. Tarakanov, Giuseppa Mudo', Antonio Jiménez-Beristain, Luigi F. Agnati, Francisco Ciruela, Natale Belluardo, Kjell Fuxe. Enhancement of the FGFR1 signaling in the FGFR1-5-HT1A heteroreceptor complex in midbrain raphe 5-HT neuron systems. Relevance for neuroplasticity and depression. Biochemical and Biophysical Research Communications. 2015; 463 (3):180-186.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Mileidys Pérez-Alea; Manuel Narvaez; Alexander O. Tarakanov; Giuseppa Mudo'; Antonio Jiménez-Beristain; Luigi F. Agnati; Francisco Ciruela; Natale Belluardo; Kjell Fuxe. 2015. "Enhancement of the FGFR1 signaling in the FGFR1-5-HT1A heteroreceptor complex in midbrain raphe 5-HT neuron systems. Relevance for neuroplasticity and depression." Biochemical and Biophysical Research Communications 463, no. 3: 180-186.
The ascending midbrain 5-HT neurons known to contain 5-HT1A autoreceptors may be dysregulated in depression due to a reduced trophic support. With in situ proximity ligation assay (PLA) and supported by co-location of the FGFR1 and 5-HT1A immunoreactivities in midbrain raphe 5-HT cells, evidence for the existence of FGFR1–5-HT1A heteroreceptor complexes were obtained in the dorsal and median raphe nuclei of the Sprague–Dawley rat. Their existence in the rat medullary raphe RN33B cell cultures was also established. After combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA positive clusters was found in the RN33B cells. Similar results were reached upon coactivation by agonists in HEK293T cells using the Fluorescent Resonance Energy Transfer (FRET) technique resulting in increased FRETmax and reduced FRET50 values. The heteroreceptor complex formation was dependent on TMV of the 5-HT1A receptor since it was blocked by incubation with TMV but not with TMII. Taken together, the 5-HT1A autoreceptors by being recruited into a FGFR1–5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells may develop a novel function, namely a trophic role in many midbrain 5-HT neuron systems originating from the dorsal and medianus raphe nuclei.
Dasiel O. Borroto-Escuela; Manuel Narvaez; Mileidys Pérez-Alea; Alexander O. Tarakanov; Antonio Jiménez-Beristain; Giuseppa Mudó; Luigi F. Agnati; Francisco Ciruela; Natale Belluardo; Kjell Fuxe. Evidence for the existence of FGFR1–5-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system. Biochemical and Biophysical Research Communications 2014, 456, 489 -493.
AMA StyleDasiel O. Borroto-Escuela, Manuel Narvaez, Mileidys Pérez-Alea, Alexander O. Tarakanov, Antonio Jiménez-Beristain, Giuseppa Mudó, Luigi F. Agnati, Francisco Ciruela, Natale Belluardo, Kjell Fuxe. Evidence for the existence of FGFR1–5-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system. Biochemical and Biophysical Research Communications. 2014; 456 (1):489-493.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Manuel Narvaez; Mileidys Pérez-Alea; Alexander O. Tarakanov; Antonio Jiménez-Beristain; Giuseppa Mudó; Luigi F. Agnati; Francisco Ciruela; Natale Belluardo; Kjell Fuxe. 2014. "Evidence for the existence of FGFR1–5-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system." Biochemical and Biophysical Research Communications 456, no. 1: 489-493.
Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor–receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist 3H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in 3H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists.
Dasiel O. Borroto-Escuela; Wilber Romero-Fernandez; Manuel Narvaez; Julia Oflijan; Luigi F. Agnati; Kjell Fuxe. Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes. Biochemical and Biophysical Research Communications 2013, 443, 278 -284.
AMA StyleDasiel O. Borroto-Escuela, Wilber Romero-Fernandez, Manuel Narvaez, Julia Oflijan, Luigi F. Agnati, Kjell Fuxe. Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes. Biochemical and Biophysical Research Communications. 2013; 443 (1):278-284.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Wilber Romero-Fernandez; Manuel Narvaez; Julia Oflijan; Luigi F. Agnati; Kjell Fuxe. 2013. "Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes." Biochemical and Biophysical Research Communications 443, no. 1: 278-284.
New findings show that neurotrophic and antidepressant effects of 5-HT in brain can, in part, be mediated by activation of the 5-HT1A receptor protomer in the hippocampal and raphe FGFR1–5-HT1A heteroreceptor complexes enhancing the FGFR1 signaling. The dynamic agonist modulation of the FGFR1–5-HT1A heteroreceptor complexes and their recruitment of β-arrestin is now determined in cellular models with focus on its impact on 5-HT1AR and FGFR1 homodimerization in the heteroreceptor complexes based on BRET2 assays. The findings show that coagonist treatment with 8-OH-DPAT and FGF2 but not treatment with the 5-HT1A agonist alone markedly increases the BRETmax values and significantly reduces the BRET50 values of 5HT1A homodimerization. The effects of FGF2 or FGF20 with or without the 5-HT1A agonist were also studied on the FGFR1 homodimerization of the heteroreceptor complexes. FGF2 produced a marked and rapid increase in FGFR1 homodimerization which partially declined over a 10 min period. Cotreatment with FGF2 and 5-HT1A agonist blocked this decline in FGFR1 homodimerization. Furthermore, FGF2 alone produced a small increase in the BRET2 signal from the 5-HT1A-β-arrestin2 receptor–protein complex which was additive to the marked effect of 8-OH-DPAT alone. Taken together, the participation of 5-HT1A and FGFR1 homodimers and recruitment of β-arrestin2 was demonstrated in the FGFR1–5-HT1A heteroreceptor complexes upon agonist treatments.
Dasiel O. Borroto-Escuela; Fidel Corrales; Manuel Narvaez; Julia Oflijan; Luigi F. Agnati; Miklós Palkovits; Kjell Fuxe. Dynamic modulation of FGFR1–5-HT1A heteroreceptor complexes. Agonist treatment enhances participation of FGFR1 and 5-HT1A homodimers and recruitment of β-arrestin2. Biochemical and Biophysical Research Communications 2013, 441, 387 -392.
AMA StyleDasiel O. Borroto-Escuela, Fidel Corrales, Manuel Narvaez, Julia Oflijan, Luigi F. Agnati, Miklós Palkovits, Kjell Fuxe. Dynamic modulation of FGFR1–5-HT1A heteroreceptor complexes. Agonist treatment enhances participation of FGFR1 and 5-HT1A homodimers and recruitment of β-arrestin2. Biochemical and Biophysical Research Communications. 2013; 441 (2):387-392.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Fidel Corrales; Manuel Narvaez; Julia Oflijan; Luigi F. Agnati; Miklós Palkovits; Kjell Fuxe. 2013. "Dynamic modulation of FGFR1–5-HT1A heteroreceptor complexes. Agonist treatment enhances participation of FGFR1 and 5-HT1A homodimers and recruitment of β-arrestin2." Biochemical and Biophysical Research Communications 441, no. 2: 387-392.
Biochemical, histochemical and coimmunoprecipitation experiments have indicated the existence of antagonistic dopamine D2 (D2R) and neurotensin 1 (NTS1R) receptor–receptor interactions in the dorsal and ventral striatum indicating a potential role of these receptor–receptor interactions in Parkinson’s disease and schizophrenia. By means of Bioluminiscence Resonance energy transfer (BRET2) evidence has for the first time been obtained in the current study for the existence of both D2LR/NTS1R and D2SR/NTS1R heteromers in living HEK293T cells. Through confocal laser microscopy the NTS1RGFP2 and D2RYFP were also shown to be colocated in the plasma membrane of these cells. A bioinformatic analysis suggests the existence of a basic set of three homology protriplets (TVM, DLL and/or LRA) in the two participating receptors which may contribute to the formation of the D2R/NTS1R heteromers by participating in guide–clasp interactions in the receptor interface. The CREB reporter gene assay indicated that the neurotensin receptor agonist JMV 449 markedly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal. In contrast, the neurotensin agonist was found to markedly increase the quinpirole potency to activate the MAPK pathway as also studied with luciferase reporter gene assay measuring the degree of SRE activity as well as with ERK1/2 phosphorylation assays. These dynamic changes in D2R signaling produced by the neurotensin receptor agonist may involve antagonistic allosteric receptor–receptor interactions in the D2LR–NTS1R heteromers at the plasma membrane level (CREB pathway) and synergistic interactions in PKC activation at the cytoplasmatic level (MAPK pathway).
Dasiel O. Borroto-Escuela; Annalisa Ravani; Alexander O. Tarakanov; Ismel Brito; Manuel Narvaez; Wilber Romero-Fernandez; Fidel Corrales; Luigi F. Agnati; Sergio Tanganelli; Luca Ferraro; Kjell Fuxe. Dopamine D2 receptor signaling dynamics of dopamine D2-neurotensin 1 receptor heteromers. Biochemical and Biophysical Research Communications 2013, 435, 140 -146.
AMA StyleDasiel O. Borroto-Escuela, Annalisa Ravani, Alexander O. Tarakanov, Ismel Brito, Manuel Narvaez, Wilber Romero-Fernandez, Fidel Corrales, Luigi F. Agnati, Sergio Tanganelli, Luca Ferraro, Kjell Fuxe. Dopamine D2 receptor signaling dynamics of dopamine D2-neurotensin 1 receptor heteromers. Biochemical and Biophysical Research Communications. 2013; 435 (1):140-146.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Annalisa Ravani; Alexander O. Tarakanov; Ismel Brito; Manuel Narvaez; Wilber Romero-Fernandez; Fidel Corrales; Luigi F. Agnati; Sergio Tanganelli; Luca Ferraro; Kjell Fuxe. 2013. "Dopamine D2 receptor signaling dynamics of dopamine D2-neurotensin 1 receptor heteromers." Biochemical and Biophysical Research Communications 435, no. 1: 140-146.
Galanin receptor (GalR) subtypes1-3 linked to central galanin neurons may form heteromers with each other and other types of G protein coupled receptors (GPCRs) in the Central Nervous System (CNS). These heteromers may be one molecular mechanism for galanin peptides and their N-terminal fragments (gal 1-15) to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional and the cardiovascular networks. GalR-5-HT1A heteromers likely exist with antagonistic GalR-5-HT1A receptor-receptor interactions in the ascending midbrain raphe 5-HT neuron systems and their target regions. They represent a novel target for antidepressant drugs. Evidence is given for the existence of GalR1-5-HT1A heteromers in cellular models with transinhibition of the protomer signaling. A GalR1-GalR2 heteromer is proposed to be a galanin N-terminal fragment preferring receptor (1-15) in the CNS. Furthermore, a GalR1-GalR2-5-HT1A heterotrimer is postulated to explain why only galanin (1-15) but not galanin (1-29) can antagonistically modulate the 5-HT1A receptors in the dorsal hippocampus rich in gal fragment binding sites. The results underline a putative role of different types of GalR-5-HT1A heteroreceptor complexes in depression. GalR antagonists may also have therapeutic actions in depression by blocking the antagonistic GalR-NPYY1 receptor interactions in putative GalR-NPYY1 receptor heteromers in the CNS resulting in increases in NPYY1 transmission and antidepressant effects. In contrast the galanin fragment receptor (a postulated GalR1-GalR2 heteromer) appears to be linked to the NPYY2 receptor enhancing the affinity of the NPYY2 binding sites in a putative GalR1-GalR2-NPYY2 heterotrimer. Finally, putative GalR-α2-adrenoreceptor heteromers with antagonistic receptor-receptor interactions may be a widespread mechanism in the CNS for integration of galanin and noradrenaline signals also of likely relevance for depression.
Kjell Fuxe; Dasiel Oscar Borroto-Escuela; Wilber Romero-Fernandez; Alexander O. Tarakanov; Feliciano Calvo; Pere Garriga; Mercé Tena; Manuel Narvaez; Carmelo Millón; Concepción Parrado; Francisco Ciruela; Luigi Francesco Agnati; Jose A. Narvaez; Zaida Díaz-Cabiale. On the existence and function of galanin receptor heteromers in the central nervous system. Frontiers in Endocrinology 2012, 3, 127 .
AMA StyleKjell Fuxe, Dasiel Oscar Borroto-Escuela, Wilber Romero-Fernandez, Alexander O. Tarakanov, Feliciano Calvo, Pere Garriga, Mercé Tena, Manuel Narvaez, Carmelo Millón, Concepción Parrado, Francisco Ciruela, Luigi Francesco Agnati, Jose A. Narvaez, Zaida Díaz-Cabiale. On the existence and function of galanin receptor heteromers in the central nervous system. Frontiers in Endocrinology. 2012; 3 ():127.
Chicago/Turabian StyleKjell Fuxe; Dasiel Oscar Borroto-Escuela; Wilber Romero-Fernandez; Alexander O. Tarakanov; Feliciano Calvo; Pere Garriga; Mercé Tena; Manuel Narvaez; Carmelo Millón; Concepción Parrado; Francisco Ciruela; Luigi Francesco Agnati; Jose A. Narvaez; Zaida Díaz-Cabiale. 2012. "On the existence and function of galanin receptor heteromers in the central nervous system." Frontiers in Endocrinology 3, no. : 127.
A single serine point mutation (S374A) in the adenosine A2A receptor (A2AR) C-terminal tail reduces A2AR–D2R heteromerization and prevents its allosteric modulation of the dopamine D2 receptor (D2R). By means of site directed mutagenesis of the A2AR and synthetic transmembrane (TM) α-helix peptides of the D2R we further explored the role of electrostatic interactions and TM helix interactions of the A2AR–D2R heteromer interface. We found evidence that the TM domains IV and V of the D2R play a major role in the A2AR–D2R heteromer interface since the incubation with peptides corresponding to these domains significantly reduced the ability of A2AR and D2R to heteromerize. In addition, the incubation with TM-IV or TM-V blocked the allosteric modulation normally found in A2AR–D2R heteromers. The mutation of two negatively charged aspartates in the A2AR C-terminal tail (D401A/D402A) in combination with the S374A mutation drastically reduced the physical A2AR–D2R interaction and lost the ability of antagonistic allosteric modulation over the A2AR–D2R interface, suggesting further evidence for the existence of an electrostatic interaction between the C-terminal tail of A2AR and the intracellular loop 3 (IL3) of D2R. On the other hand, molecular dynamic model and bioinformatic analysis propose that specific AAR, AQE, and VLS protriplets as an important motive in the A2AR–D2LR heteromer interface together with D2LR TM segments IV/V interacting with A2AR TM-IV/V or TM-I/VII.
Dasiel O. Borroto-Escuela; Wilber Romero-Fernandez; Alexander O. Tarakanov; Maricel Gómez-Soler; Fidel Corrales; Daniel Marcellino; Manuel Narvaez; Malgorzata Frankowska; Marc Flajolet; Nathaniel Heintz; Luigi F. Agnati; Francisco Ciruela; Kjell Fuxe. Characterization of the A2AR–D2R interface: Focus on the role of the C-terminal tail and the transmembrane helices. Biochemical and Biophysical Research Communications 2010, 402, 801 -807.
AMA StyleDasiel O. Borroto-Escuela, Wilber Romero-Fernandez, Alexander O. Tarakanov, Maricel Gómez-Soler, Fidel Corrales, Daniel Marcellino, Manuel Narvaez, Malgorzata Frankowska, Marc Flajolet, Nathaniel Heintz, Luigi F. Agnati, Francisco Ciruela, Kjell Fuxe. Characterization of the A2AR–D2R interface: Focus on the role of the C-terminal tail and the transmembrane helices. Biochemical and Biophysical Research Communications. 2010; 402 (4):801-807.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Wilber Romero-Fernandez; Alexander O. Tarakanov; Maricel Gómez-Soler; Fidel Corrales; Daniel Marcellino; Manuel Narvaez; Malgorzata Frankowska; Marc Flajolet; Nathaniel Heintz; Luigi F. Agnati; Francisco Ciruela; Kjell Fuxe. 2010. "Characterization of the A2AR–D2R interface: Focus on the role of the C-terminal tail and the transmembrane helices." Biochemical and Biophysical Research Communications 402, no. 4: 801-807.
Evidence exists that the adenosine receptor A2AR and the dopamine receptor D2R form constitutive heteromers in living cells. Mass spectrometry and pull-down data showed that an arginine-rich domain of the D2R third intracellular loop binds via electrostatic interactions to a specific motif of the A2AR C-terminal tail. It has been indicated that the phosphorylated serine 374 might represent an important residue in this motif. In the present study, it was found that a point mutation of serine 374 to alanine reduced the A2AR ability to interact with D2R. Also, this point mutation abolished the A2AR-mediated inhibition of both the D2R high affinity agonist binding and signaling. These results point to a key role of serine 374 in the A2AR–D2R interface. All together these results indicate that by targeting A2AR serine 374 it will be possible to allosterically modulate A2AR–D2R function, thus representing a new approach for therapeutically modulate D2R function.
Dasiel O. Borroto-Escuela; Daniel Marcellino; Manuel Narvaez; Marc Flajolet; Nathaniel Heintz; Luigi Agnati; Francisco Ciruela; Kjell Fuxe. A serine point mutation in the adenosine A2AR C-terminal tail reduces receptor heteromerization and allosteric modulation of the dopamine D2R. Biochemical and Biophysical Research Communications 2010, 394, 222 -227.
AMA StyleDasiel O. Borroto-Escuela, Daniel Marcellino, Manuel Narvaez, Marc Flajolet, Nathaniel Heintz, Luigi Agnati, Francisco Ciruela, Kjell Fuxe. A serine point mutation in the adenosine A2AR C-terminal tail reduces receptor heteromerization and allosteric modulation of the dopamine D2R. Biochemical and Biophysical Research Communications. 2010; 394 (1):222-227.
Chicago/Turabian StyleDasiel O. Borroto-Escuela; Daniel Marcellino; Manuel Narvaez; Marc Flajolet; Nathaniel Heintz; Luigi Agnati; Francisco Ciruela; Kjell Fuxe. 2010. "A serine point mutation in the adenosine A2AR C-terminal tail reduces receptor heteromerization and allosteric modulation of the dopamine D2R." Biochemical and Biophysical Research Communications 394, no. 1: 222-227.