The Experts below are selected from a list of 4983 Experts worldwide ranked by ideXlab platform
Kjell Fuxe - One of the best experts on this subject based on the ideXlab platform.
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adenosine heteroreceptor complexes in the basal ganglia are implicated in parkinson s disease and its treatment
Journal of Neural Transmission, 2019Co-Authors: Dasiel O Borrotoescuela, Kjell FuxeAbstract:The adenosine homo, iso and heteroreceptor complexes in the basal ganglia play a highly significant role in modulating the indirect and direct pathways and the striosomal projections to the nigro-striatal DA system. The major adenosine receptor complexes in the striato-pallidal GABA neurons can be the A2AR–D2R and A2AR–D2R–mGluR5 receptor complexes, in which A2AR Protomers and mGluR5 Protomers can allosterically interact to inhibit D2R Protomer signaling. Through a reorganization of these heteroreceptor complexes upon chronic dopaminergic treatment a pathological and prolonged inhibition of D2R receptor Protomer signaling can develop with motor inhibition and wearing off of the therapeutic effects of levodopa and dopamine receptor agonists. The direct pathway is enriched in D1R in and around glutamate synapses enhancing the ability of these GABA neurons to be activated and increase motor initiation. The brake on these GABA neurons is in this case exerted by A1R forming A1R–D1R heteroreceptor complexes in which they allosterically inhibit D1R signaling and thereby reduce motor initiation. Upon chronic levodopa treatment a reorganization of the D1R heteroreceptor complexes develops with the formation of putative A1R–D1R–D3 in addition to D1R–D3R complexes in which D3R enhances D1R Protomer signaling and may make the A1R Protomer brake less effective. Alpha-synuclein monomers–dimers are postulated to form complexes with A2AR homo and heteroProtomers in the plasma membrane enhancing alpha-synuclein aggregation and toxicity. The alpha-synuclein fibrils formed in the A2AR enriched dendritic spines of the striato-pallidal GABA neurons may reach the surrounding DA terminals via extracellular-vesicle-mediated volume transmission involving internalization of the vesicles and their cargo (alpha-synuclein fibrils) into the vulnerable DA terminals, enhancing their degeneration followed by retrograde flow of these fibrils in the DA axons to the vulnerable nigral DA nerve cells.
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Diversity and bias through dopamine D2R heteroreceptor complexes.
Current opinion in pharmacology, 2016Co-Authors: Dasiel O Borroto-escuela, Kjell FuxeAbstract:The D2R is a hub receptor interacting with a large number of other GPCRs. A2AR activation of the antagonistic A2AR–D2R interaction not only leads to inhibition of the Gi/o signaling but also to an increase in β-arrestin2 signaling over the D2R Protomer. Hallucinogenic 5-HT2AR agonists can produce a biased agonist state at the 5-HT2AR Protomer of D2R–5-HT2AR heteroreceptor complexes with increased D2R recognition and Gi/o mediated signaling. Allosteric receptor–receptor interactions in D2-NTR1 heteroreceptor complexes inhibit D2R function and can switch G protein coupling. These large numbers of D2R heterocomplexes and their allosteric receptor–receptor interactions produce a marked increase in diversity and bias of the participating D2R Protomers opening a promised land for drug development in schizophrenia, addiction and Parkinson's disease.
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Diversity and Bias through Receptor-Receptor Interactions in GPCR Heteroreceptor Complexes. Focus on Examples from Dopamine D2 Receptor Heteromerization.
Frontiers in endocrinology, 2014Co-Authors: Kjell Fuxe, Alexander O. Tarakanov, Luigi Francesco Agnati, Luca Ferraro, Sergio Tanganelli, Małgorzata Filip, Zaida Díaz-cabiale, Wilber Romero Fernandez, Pere Garriga, Dasiel O Borroto-escuelaAbstract:Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the Protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the receptor Protomer repertoire leading to diversity and biased recognition and signaling. In 1980ies and 1990ies it was shown that neurotensin through selective antagonistic NTR-D2likeR interactions increased the diversity of DA signalling by reducing D2R mediated dopamine signalling over D1R mediated dopamine signalling. Furthermore, D2R Protomer appeared to bias the specificity of the NTR orthosteric binding site towards neuromedin N vs neurotensin in the heteroreceptor complex. Complex CCK2R-D1R-D2R interactions in possible heteroreceptor complexes were also demonstrated further increasing receptor diversity. In D2R-5-HT2AR heteroreceptor complexes the hallucinogenic 5-HT2AR agonists LSD and DOI were recently found to exert a biased agonist action on the orthosteric site of the 5-HT2AR Protomer leading to the development of an active conformational state different from the one produced by 5-HT. Furthermore, as recently demonstrated allosteric A2A-D2R receptor-receptor interaction brought about not only a reduced affinity of the D2R agonist binding site but also a biased modulation of the D2R Protomer signalling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced which moved away from Gi/o signaling and instead favoured b-arrestin2 mediated signalling. These examples on allosteric receptor-receptor interactions obtained over several decades serve to illustrate the significant increase in diversity and biased recognition and signaling that develop through such mechanisms.
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dopamine d2 heteroreceptor complexes and their receptor receptor interactions in ventral striatum novel targets for antipsychotic drugs
Progress in Brain Research, 2014Co-Authors: Kjell Fuxe, Alexander O. Tarakanov, Luca Ferraro, Sergio Tanganelli, Michael Di Palma, Dasiel O Borrotoescuela, Wilber Romerofernandez, Mileidys Perezalea, Luigi Francesco AgnatiAbstract:Abstract 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.
Dasiel O Borrotoescuela - One of the best experts on this subject based on the ideXlab platform.
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adenosine heteroreceptor complexes in the basal ganglia are implicated in parkinson s disease and its treatment
Journal of Neural Transmission, 2019Co-Authors: Dasiel O Borrotoescuela, Kjell FuxeAbstract:The adenosine homo, iso and heteroreceptor complexes in the basal ganglia play a highly significant role in modulating the indirect and direct pathways and the striosomal projections to the nigro-striatal DA system. The major adenosine receptor complexes in the striato-pallidal GABA neurons can be the A2AR–D2R and A2AR–D2R–mGluR5 receptor complexes, in which A2AR Protomers and mGluR5 Protomers can allosterically interact to inhibit D2R Protomer signaling. Through a reorganization of these heteroreceptor complexes upon chronic dopaminergic treatment a pathological and prolonged inhibition of D2R receptor Protomer signaling can develop with motor inhibition and wearing off of the therapeutic effects of levodopa and dopamine receptor agonists. The direct pathway is enriched in D1R in and around glutamate synapses enhancing the ability of these GABA neurons to be activated and increase motor initiation. The brake on these GABA neurons is in this case exerted by A1R forming A1R–D1R heteroreceptor complexes in which they allosterically inhibit D1R signaling and thereby reduce motor initiation. Upon chronic levodopa treatment a reorganization of the D1R heteroreceptor complexes develops with the formation of putative A1R–D1R–D3 in addition to D1R–D3R complexes in which D3R enhances D1R Protomer signaling and may make the A1R Protomer brake less effective. Alpha-synuclein monomers–dimers are postulated to form complexes with A2AR homo and heteroProtomers in the plasma membrane enhancing alpha-synuclein aggregation and toxicity. The alpha-synuclein fibrils formed in the A2AR enriched dendritic spines of the striato-pallidal GABA neurons may reach the surrounding DA terminals via extracellular-vesicle-mediated volume transmission involving internalization of the vesicles and their cargo (alpha-synuclein fibrils) into the vulnerable DA terminals, enhancing their degeneration followed by retrograde flow of these fibrils in the DA axons to the vulnerable nigral DA nerve cells.
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receptor receptor interactions in multiple 5 ht1a heteroreceptor complexes in raphe hippocampal 5 ht transmission and their relevance for depression and its treatment
Molecules, 2018Co-Authors: Luca Ferraro, Dasiel O Borrotoescuela, Wilber Romerofernandez, Ismel Brito, Manuel Narváez, Patrizia Ambrogini, Yuniesky Andradetalavera, Antonio Floresburgess, Carmelo MillónAbstract: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.
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dopamine d2 heteroreceptor complexes and their receptor receptor interactions in ventral striatum novel targets for antipsychotic drugs
Progress in Brain Research, 2014Co-Authors: Kjell Fuxe, Alexander O. Tarakanov, Luca Ferraro, Sergio Tanganelli, Michael Di Palma, Dasiel O Borrotoescuela, Wilber Romerofernandez, Mileidys Perezalea, Luigi Francesco AgnatiAbstract:Abstract 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.
Dasiel O Borroto-escuela - One of the best experts on this subject based on the ideXlab platform.
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Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment
Molecules (Basel Switzerland), 2018Co-Authors: Dasiel O Borroto-escuela, Wilber Romero-fernandez, Luca Ferraro, Ismel Brito, Manuel Narváez, Patrizia Ambrogini, Yuniesky Andrade-talavera, Antonio Flores-burgess, Carmelo Millón, Belén GagoAbstract: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.
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Diversity and bias through dopamine D2R heteroreceptor complexes.
Current opinion in pharmacology, 2016Co-Authors: Dasiel O Borroto-escuela, Kjell FuxeAbstract:The D2R is a hub receptor interacting with a large number of other GPCRs. A2AR activation of the antagonistic A2AR–D2R interaction not only leads to inhibition of the Gi/o signaling but also to an increase in β-arrestin2 signaling over the D2R Protomer. Hallucinogenic 5-HT2AR agonists can produce a biased agonist state at the 5-HT2AR Protomer of D2R–5-HT2AR heteroreceptor complexes with increased D2R recognition and Gi/o mediated signaling. Allosteric receptor–receptor interactions in D2-NTR1 heteroreceptor complexes inhibit D2R function and can switch G protein coupling. These large numbers of D2R heterocomplexes and their allosteric receptor–receptor interactions produce a marked increase in diversity and bias of the participating D2R Protomers opening a promised land for drug development in schizophrenia, addiction and Parkinson's disease.
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Diversity and Bias through Receptor-Receptor Interactions in GPCR Heteroreceptor Complexes. Focus on Examples from Dopamine D2 Receptor Heteromerization.
Frontiers in endocrinology, 2014Co-Authors: Kjell Fuxe, Alexander O. Tarakanov, Luigi Francesco Agnati, Luca Ferraro, Sergio Tanganelli, Małgorzata Filip, Zaida Díaz-cabiale, Wilber Romero Fernandez, Pere Garriga, Dasiel O Borroto-escuelaAbstract:Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the Protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the receptor Protomer repertoire leading to diversity and biased recognition and signaling. In 1980ies and 1990ies it was shown that neurotensin through selective antagonistic NTR-D2likeR interactions increased the diversity of DA signalling by reducing D2R mediated dopamine signalling over D1R mediated dopamine signalling. Furthermore, D2R Protomer appeared to bias the specificity of the NTR orthosteric binding site towards neuromedin N vs neurotensin in the heteroreceptor complex. Complex CCK2R-D1R-D2R interactions in possible heteroreceptor complexes were also demonstrated further increasing receptor diversity. In D2R-5-HT2AR heteroreceptor complexes the hallucinogenic 5-HT2AR agonists LSD and DOI were recently found to exert a biased agonist action on the orthosteric site of the 5-HT2AR Protomer leading to the development of an active conformational state different from the one produced by 5-HT. Furthermore, as recently demonstrated allosteric A2A-D2R receptor-receptor interaction brought about not only a reduced affinity of the D2R agonist binding site but also a biased modulation of the D2R Protomer signalling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced which moved away from Gi/o signaling and instead favoured b-arrestin2 mediated signalling. These examples on allosteric receptor-receptor interactions obtained over several decades serve to illustrate the significant increase in diversity and biased recognition and signaling that develop through such mechanisms.
Luca Ferraro - One of the best experts on this subject based on the ideXlab platform.
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receptor receptor interactions in multiple 5 ht1a heteroreceptor complexes in raphe hippocampal 5 ht transmission and their relevance for depression and its treatment
Molecules, 2018Co-Authors: Luca Ferraro, Dasiel O Borrotoescuela, Wilber Romerofernandez, Ismel Brito, Manuel Narváez, Patrizia Ambrogini, Yuniesky Andradetalavera, Antonio Floresburgess, Carmelo MillónAbstract: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.
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Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment
Molecules (Basel Switzerland), 2018Co-Authors: Dasiel O Borroto-escuela, Wilber Romero-fernandez, Luca Ferraro, Ismel Brito, Manuel Narváez, Patrizia Ambrogini, Yuniesky Andrade-talavera, Antonio Flores-burgess, Carmelo Millón, Belén GagoAbstract: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.
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Diversity and Bias through Receptor-Receptor Interactions in GPCR Heteroreceptor Complexes. Focus on Examples from Dopamine D2 Receptor Heteromerization.
Frontiers in endocrinology, 2014Co-Authors: Kjell Fuxe, Alexander O. Tarakanov, Luigi Francesco Agnati, Luca Ferraro, Sergio Tanganelli, Małgorzata Filip, Zaida Díaz-cabiale, Wilber Romero Fernandez, Pere Garriga, Dasiel O Borroto-escuelaAbstract:Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the Protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the receptor Protomer repertoire leading to diversity and biased recognition and signaling. In 1980ies and 1990ies it was shown that neurotensin through selective antagonistic NTR-D2likeR interactions increased the diversity of DA signalling by reducing D2R mediated dopamine signalling over D1R mediated dopamine signalling. Furthermore, D2R Protomer appeared to bias the specificity of the NTR orthosteric binding site towards neuromedin N vs neurotensin in the heteroreceptor complex. Complex CCK2R-D1R-D2R interactions in possible heteroreceptor complexes were also demonstrated further increasing receptor diversity. In D2R-5-HT2AR heteroreceptor complexes the hallucinogenic 5-HT2AR agonists LSD and DOI were recently found to exert a biased agonist action on the orthosteric site of the 5-HT2AR Protomer leading to the development of an active conformational state different from the one produced by 5-HT. Furthermore, as recently demonstrated allosteric A2A-D2R receptor-receptor interaction brought about not only a reduced affinity of the D2R agonist binding site but also a biased modulation of the D2R Protomer signalling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced which moved away from Gi/o signaling and instead favoured b-arrestin2 mediated signalling. These examples on allosteric receptor-receptor interactions obtained over several decades serve to illustrate the significant increase in diversity and biased recognition and signaling that develop through such mechanisms.
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dopamine d2 heteroreceptor complexes and their receptor receptor interactions in ventral striatum novel targets for antipsychotic drugs
Progress in Brain Research, 2014Co-Authors: Kjell Fuxe, Alexander O. Tarakanov, Luca Ferraro, Sergio Tanganelli, Michael Di Palma, Dasiel O Borrotoescuela, Wilber Romerofernandez, Mileidys Perezalea, Luigi Francesco AgnatiAbstract:Abstract 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.
Marcos N Eberlin - One of the best experts on this subject based on the ideXlab platform.
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Protomers formation separation and characterization via travelling wave ion mobility mass spectrometry
Journal of Mass Spectrometry, 2012Co-Authors: Priscila M Lalli, Bernardo A Iglesias, Henrique E Toma, Romeu J Daroda, Juvenal Carolino Da Silva Filho, Jan E Szulejko, Koiti Araki, Marcos N EberlinAbstract:Travelling wave ion mobility mass spectrometry (TWIM-MS) with post-TWIM and pre-TWIM collision-induced dissociation (CID) experiments were used to form, separate and characterize Protomers sampled directly from solutions or generated in the gas phase via CID. When in solution equilibria, these species were transferred to the gas phase via electrospray ionization, and then separated by TWIM-MS. CID performed after TWIM separation (post-TWIM) allowed the characterization of both Protomers via structurally diagnostic fragments. Protonated aniline (1) sampled from solution was found to be constituted of a ca. 5:1 mixture of two gaseous Protomers, that is, the N-protonated (1a) and ring protonated (1b) molecules, respectively. When dissociated, 1a nearly exclusively loses NH(3) , whereas 1b displays a much diverse set of fragments. When formed via CID, varying populations of 1a and 1b were detected. Two co-existing Protomers of two isomeric porphyrins were also separated and characterized via post-TWIM CID. A deprotonated porphyrin sampled from a basic methanolic solution was found to be constituted predominantly of the Protomer arising from deprotonation at the carboxyl group, which dissociates promptly by CO(2) loss, but a CID-resistant Protomer arising from deprotonation at a porphyrinic ring NH was also detected and characterized. The doubly deprotonated porphyrin was found to be constituted predominantly of a single Protomer arising from deprotonation of two carboxyl groups.
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Protomers formation separation and characterization via travelling wave ion mobility mass spectrometry
Journal of Mass Spectrometry, 2012Co-Authors: Priscila M Lalli, Bernardo A Iglesias, Henrique E Toma, Romeu J Daroda, Juvenal Carolino Da Silva Filho, Jan E Szulejko, Koiti Araki, Marcos N EberlinAbstract:Travelling wave ion mobility mass spectrometry (TWIM-MS) with post-TWIM and pre-TWIM collision-induced dissociation (CID) experiments were used to form, separate and characterize Protomers sampled directly from solutions or generated in the gas phase via CID. When in solution equilibria, these species were transferred to the gas phase via electrospray ionization, and then separated by TWIM-MS. CID performed after TWIM separation (post-TWIM) allowed the characterization of both Protomers via structurally diagnostic fragments. Protonated aniline (1) sampled from solution was found to be constituted of a ca. 5:1 mixture of two gaseous Protomers, that is, the N-protonated (1a) and ring protonated (1b) molecules, respectively. When dissociated, 1a nearly exclusively loses NH3, whereas 1b displays a much diverse set of fragments. When formed via CID, varying populations of 1a and 1b were detected. Two co-existing Protomers of two isomeric porphyrins were also separated and characterized via post-TWIM CID. A deprotonated porphyrin sampled from a basic methanolic solution was found to be constituted predominantly of the Protomer arising from deprotonation at the carboxyl group, which dissociates promptly by CO2 loss, but a CID-resistant Protomer arising from deprotonation at a porphyrinic ring NH was also detected and characterized. The doubly deprotonated porphyrin was found to be constituted predominantly of a single Protomer arising from deprotonation of two carboxyl groups. Copyright © 2012 John Wiley & Sons, Ltd.
