Publications from the Integrative Neurobiology Section.
2023
Ferré, Sergi; Köfalvi, Attila; Ciruela, Francisco; Justinova, Zuzana; Pistis, Marco
Targeting corticostriatal transmission for the treatment of cannabinoid use disorder Journal Article
In: Trends in Pharmacological Sciences, vol. 44, no. 8, pp. 495-506, 2023, ISSN: 0165-6147.
@article{FERRE2023495,
title = {Targeting corticostriatal transmission for the treatment of cannabinoid use disorder},
author = {Sergi Ferré and Attila Köfalvi and Francisco Ciruela and Zuzana Justinova and Marco Pistis},
url = {https://pubmed.ncbi.nlm.nih.gov/37331914/},
doi = {https://doi.org/10.1016/j.tips.2023.05.003},
issn = {0165-6147},
year = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Trends in Pharmacological Sciences},
volume = {44},
number = {8},
pages = {495-506},
abstract = {It is generally assumed that the rewarding effects of cannabinoids are mediated by cannabinoid CB1 receptors (CB1Rs) the activation of which disinhibits dopaminergic neurons in the ventral tegmental area (VTA). However, this mechanism cannot fully explain novel results indicating that dopaminergic neurons also mediate the aversive effects of cannabinoids in rodents, and previous results showing that preferentially presynaptic adenosine A2A receptor (A2AR) antagonists counteract self-administration of Δ-9-tetrahydrocannabinol (THC) in nonhuman primates (NHPs). Based on recent experiments in rodents and imaging studies in humans, we propose that the activation of frontal corticostriatal glutamatergic transmission constitutes an additional and necessary mechanism. Here, we review evidence supporting the involvement of cortical astrocytic CB1Rs in the activation of corticostriatal neurons and that A2AR receptor heteromers localized in striatal glutamatergic terminals mediate the counteracting effects of the presynaptic A2AR antagonists, constituting potential targets for the treatment of cannabinoid use disorder (CUD).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
It is generally assumed that the rewarding effects of cannabinoids are mediated by cannabinoid CB1 receptors (CB1Rs) the activation of which disinhibits dopaminergic neurons in the ventral tegmental area (VTA). However, this mechanism cannot fully explain novel results indicating that dopaminergic neurons also mediate the aversive effects of cannabinoids in rodents, and previous results showing that preferentially presynaptic adenosine A2A receptor (A2AR) antagonists counteract self-administration of Δ-9-tetrahydrocannabinol (THC) in nonhuman primates (NHPs). Based on recent experiments in rodents and imaging studies in humans, we propose that the activation of frontal corticostriatal glutamatergic transmission constitutes an additional and necessary mechanism. Here, we review evidence supporting the involvement of cortical astrocytic CB1Rs in the activation of corticostriatal neurons and that A2AR receptor heteromers localized in striatal glutamatergic terminals mediate the counteracting effects of the presynaptic A2AR antagonists, constituting potential targets for the treatment of cannabinoid use disorder (CUD).
2021
Ferré, Sergi; Ciruela, Francisco; Dessauer, Carmen W; González-Maeso, Javier; Hébert, Terence E; Jockers, Ralf; Logothetis, Diomedes E; Pardo, Leonardo
G protein-coupled receptor-effector macromolecular membrane assemblies (GEMMAs) Journal Article
In: Pharmacol Ther, pp. 107977, 2021, ISSN: 1879-016X.
@article{pmid34480967,
title = {G protein-coupled receptor-effector macromolecular membrane assemblies (GEMMAs)},
author = {Sergi Ferré and Francisco Ciruela and Carmen W Dessauer and Javier González-Maeso and Terence E Hébert and Ralf Jockers and Diomedes E Logothetis and Leonardo Pardo},
url = {https://pubmed.ncbi.nlm.nih.gov/34480967/},
doi = {10.1016/j.pharmthera.2021.107977},
issn = {1879-016X},
year = {2021},
date = {2021-09-01},
urldate = {2021-09-01},
journal = {Pharmacol Ther},
pages = {107977},
abstract = {G protein-coupled receptors (GPCRs) are the largest group of receptors involved in cellular signaling across the plasma membrane and a major class of drug targets. The canonical model for GPCR signaling involves three components - the GPCR, a heterotrimeric G protein and a proximal plasma membrane effector - that have been generally thought to be freely mobile molecules able to interact by 'collision coupling'. Here, we synthesize evidence that supports the existence of GPCR-effector macromolecular membrane assemblies (GEMMAs) comprised of specific GPCRs, G proteins, plasma membrane effector molecules and other associated transmembrane proteins that are pre-assembled prior to receptor activation by agonists, which then leads to subsequent rearrangement of the GEMMA components. The GEMMA concept offers an alternative and complementary model to the canonical collision-coupling model, allowing more efficient interactions between specific signaling components, as well as the integration of the concept of GPCR oligomerization as well as GPCR interactions with orphan receptors, truncated GPCRs and other membrane-localized GPCR-associated proteins. Collision-coupling and pre-assembled mechanisms are not exclusive and likely both operate in the cell, providing a spectrum of signaling modalities which explains the differential properties of a multitude of GPCRs in their different cellular environments. Here, we explore the unique pharmacological characteristics of individual GEMMAs, which could provide new opportunities to therapeutically modulate GPCR signaling.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
G protein-coupled receptors (GPCRs) are the largest group of receptors involved in cellular signaling across the plasma membrane and a major class of drug targets. The canonical model for GPCR signaling involves three components - the GPCR, a heterotrimeric G protein and a proximal plasma membrane effector - that have been generally thought to be freely mobile molecules able to interact by 'collision coupling'. Here, we synthesize evidence that supports the existence of GPCR-effector macromolecular membrane assemblies (GEMMAs) comprised of specific GPCRs, G proteins, plasma membrane effector molecules and other associated transmembrane proteins that are pre-assembled prior to receptor activation by agonists, which then leads to subsequent rearrangement of the GEMMA components. The GEMMA concept offers an alternative and complementary model to the canonical collision-coupling model, allowing more efficient interactions between specific signaling components, as well as the integration of the concept of GPCR oligomerization as well as GPCR interactions with orphan receptors, truncated GPCRs and other membrane-localized GPCR-associated proteins. Collision-coupling and pre-assembled mechanisms are not exclusive and likely both operate in the cell, providing a spectrum of signaling modalities which explains the differential properties of a multitude of GPCRs in their different cellular environments. Here, we explore the unique pharmacological characteristics of individual GEMMAs, which could provide new opportunities to therapeutically modulate GPCR signaling.
2020
Köfalvi, Attila; Moreno, Estefanía; Cordomí, Arnau; Cai, Ning-Sheng; Fernández-Dueñas, Victor; Ferreira, Samira G; Guixà-González, Ramón; Sánchez-Soto, Marta; Yano, Hideaki; Casadó-Anguera, Verònica; Cunha, Rodrigo A; Sebastião, Ana Maria; Ciruela, Francisco; Pardo, Leonardo; Casadó, Vicent; Ferré, Sergi
Control of glutamate release by complexes of adenosine and cannabinoid receptors Journal Article
In: BMC Biol, vol. 18, no. 1, pp. 9, 2020, ISSN: 1741-7007.
@article{pmid31973708,
title = {Control of glutamate release by complexes of adenosine and cannabinoid receptors},
author = {Attila Köfalvi and Estefanía Moreno and Arnau Cordomí and Ning-Sheng Cai and Victor Fernández-Dueñas and Samira G Ferreira and Ramón Guixà-González and Marta Sánchez-Soto and Hideaki Yano and Verònica Casadó-Anguera and Rodrigo A Cunha and Ana Maria Sebastião and Francisco Ciruela and Leonardo Pardo and Vicent Casadó and Sergi Ferré},
url = {https://pubmed.ncbi.nlm.nih.gov/31973708/},
doi = {10.1186/s12915-020-0739-0},
issn = {1741-7007},
year = {2020},
date = {2020-01-01},
urldate = {2020-01-01},
journal = {BMC Biol},
volume = {18},
number = {1},
pages = {9},
abstract = {BACKGROUND: It has been hypothesized that heteromers of adenosine A receptors (A2AR) and cannabinoid CB receptors (CB1R) localized in glutamatergic nerve terminals mediate the integration of adenosine and endocannabinoid signaling involved in the modulation of striatal excitatory neurotransmission. Previous studies have demonstrated the existence of A2AR-CB1R heteromers in artificial cell systems. A dependence of A2AR signaling for the Gi protein-mediated CB1R signaling was described as one of its main biochemical characteristics. However, recent studies have questioned the localization of functionally significant A2AR-CB1R heteromers in striatal glutamatergic terminals.
RESULTS: Using a peptide-interfering approach combined with biophysical and biochemical techniques in mammalian transfected cells and computational modeling, we could establish a tetrameric quaternary structure of the A2AR-CB1R heterotetramer. This quaternary structure was different to the also tetrameric structure of heteromers of A2AR with adenosine A receptors or dopamine D receptors, with different heteromeric or homomeric interfaces. The specific quaternary structure of the A2A-CB1R, which depended on intermolecular interactions involving the long C-terminus of the A2AR, determined a significant A2AR and Gs protein-mediated constitutive activation of adenylyl cyclase. Using heteromer-interfering peptides in experiments with striatal glutamatergic terminals, we could then demonstrate the presence of functionally significant A2AR-CB1R heteromers with the same biochemical characteristics of those studied in mammalian transfected cells. First, either an A2AR agonist or an A2AR antagonist allosterically counteracted Gi-mediated CB1R agonist-induced inhibition of depolarization-induced glutamate release. Second, co-application of both an A2AR agonist and an antagonist cancelled each other effects. Finally, a CB1R agonist inhibited glutamate release dependent on a constitutive activation of A2AR by a canonical Gs-Gi antagonistic interaction at the adenylyl cyclase level.
CONCLUSIONS: We demonstrate that the well-established cannabinoid-induced inhibition of striatal glutamate release can mostly be explained by a CB1R-mediated counteraction of the A2AR-mediated constitutive activation of adenylyl cyclase in the A2AR-CB1R heteromer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: It has been hypothesized that heteromers of adenosine A receptors (A2AR) and cannabinoid CB receptors (CB1R) localized in glutamatergic nerve terminals mediate the integration of adenosine and endocannabinoid signaling involved in the modulation of striatal excitatory neurotransmission. Previous studies have demonstrated the existence of A2AR-CB1R heteromers in artificial cell systems. A dependence of A2AR signaling for the Gi protein-mediated CB1R signaling was described as one of its main biochemical characteristics. However, recent studies have questioned the localization of functionally significant A2AR-CB1R heteromers in striatal glutamatergic terminals.
RESULTS: Using a peptide-interfering approach combined with biophysical and biochemical techniques in mammalian transfected cells and computational modeling, we could establish a tetrameric quaternary structure of the A2AR-CB1R heterotetramer. This quaternary structure was different to the also tetrameric structure of heteromers of A2AR with adenosine A receptors or dopamine D receptors, with different heteromeric or homomeric interfaces. The specific quaternary structure of the A2A-CB1R, which depended on intermolecular interactions involving the long C-terminus of the A2AR, determined a significant A2AR and Gs protein-mediated constitutive activation of adenylyl cyclase. Using heteromer-interfering peptides in experiments with striatal glutamatergic terminals, we could then demonstrate the presence of functionally significant A2AR-CB1R heteromers with the same biochemical characteristics of those studied in mammalian transfected cells. First, either an A2AR agonist or an A2AR antagonist allosterically counteracted Gi-mediated CB1R agonist-induced inhibition of depolarization-induced glutamate release. Second, co-application of both an A2AR agonist and an antagonist cancelled each other effects. Finally, a CB1R agonist inhibited glutamate release dependent on a constitutive activation of A2AR by a canonical Gs-Gi antagonistic interaction at the adenylyl cyclase level.
CONCLUSIONS: We demonstrate that the well-established cannabinoid-induced inhibition of striatal glutamate release can mostly be explained by a CB1R-mediated counteraction of the A2AR-mediated constitutive activation of adenylyl cyclase in the A2AR-CB1R heteromer.
RESULTS: Using a peptide-interfering approach combined with biophysical and biochemical techniques in mammalian transfected cells and computational modeling, we could establish a tetrameric quaternary structure of the A2AR-CB1R heterotetramer. This quaternary structure was different to the also tetrameric structure of heteromers of A2AR with adenosine A receptors or dopamine D receptors, with different heteromeric or homomeric interfaces. The specific quaternary structure of the A2A-CB1R, which depended on intermolecular interactions involving the long C-terminus of the A2AR, determined a significant A2AR and Gs protein-mediated constitutive activation of adenylyl cyclase. Using heteromer-interfering peptides in experiments with striatal glutamatergic terminals, we could then demonstrate the presence of functionally significant A2AR-CB1R heteromers with the same biochemical characteristics of those studied in mammalian transfected cells. First, either an A2AR agonist or an A2AR antagonist allosterically counteracted Gi-mediated CB1R agonist-induced inhibition of depolarization-induced glutamate release. Second, co-application of both an A2AR agonist and an antagonist cancelled each other effects. Finally, a CB1R agonist inhibited glutamate release dependent on a constitutive activation of A2AR by a canonical Gs-Gi antagonistic interaction at the adenylyl cyclase level.
CONCLUSIONS: We demonstrate that the well-established cannabinoid-induced inhibition of striatal glutamate release can mostly be explained by a CB1R-mediated counteraction of the A2AR-mediated constitutive activation of adenylyl cyclase in the A2AR-CB1R heteromer.
2019
Ferré, Sergi
Pre-coupling of receptor oligomers and signaling molecules [Video file]. Online
The Biomedical & Life Sciences Collection, Henry Stewart Talks. 2019, visited: 02.04.2019.
@online{Ferré2019,
title = {Pre-coupling of receptor oligomers and signaling molecules [Video file].},
author = {Ferré, Sergi},
url = {https://hstalks.com/bs/3908/},
year = {2019},
date = {2019-04-02},
urldate = {2019-04-02},
journal = {In: The Biomedical & Life Sciences Collection, Henry Stewart Talks.},
organization = {The Biomedical & Life Sciences Collection, Henry Stewart Talks.},
keywords = {},
pubstate = {published},
tppubtype = {online}
}
Cai, Ning-Sheng; Quiroz, Cesar; Bonaventura, Jordi; Bonifazi, Alessandro; Cole, Thomas O; Purks, Julia; Billing, Amy S; Massey, Ebonie; Wagner, Michael; Wish, Eric D; Guitart, Xavier; Rea, William; Lam, Sherry; Moreno, Estefania; Casado-Anguera, Veronica; Greenblatt, Aaron D; Jacobson, Arthur E; Rice, Kenner C; Casado, Vicent; Newman, Amy Hauck; Winkelman, John W; Michaelides, Michael; Weintraub, Eric; Volkow, Nora D; Belcher, Annabelle M; Ferre, Sergi
Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids. Journal Article
In: J Clin Invest, vol. 130, 2019, ISSN: 1558-8238 (Electronic); 0021-9738 (Linking).
@article{Cai:2019aab,
title = {Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids.},
author = {Ning-Sheng Cai and Cesar Quiroz and Jordi Bonaventura and Alessandro Bonifazi and Thomas O Cole and Julia Purks and Amy S Billing and Ebonie Massey and Michael Wagner and Eric D Wish and Xavier Guitart and William Rea and Sherry Lam and Estefania Moreno and Veronica Casado-Anguera and Aaron D Greenblatt and Arthur E Jacobson and Kenner C Rice and Vicent Casado and Amy Hauck Newman and John W Winkelman and Michael Michaelides and Eric Weintraub and Nora D Volkow and Annabelle M Belcher and Sergi Ferre},
url = {https://www.ncbi.nlm.nih.gov/pubmed/30913037},
doi = {10.1172/JCI126912},
issn = {1558-8238 (Electronic); 0021-9738 (Linking)},
year = {2019},
date = {2019-03-26},
urldate = {2019-03-26},
journal = {J Clin Invest},
volume = {130},
abstract = {Identifying non-addictive opioid medications is a high priority in medical sciences, but mu-opioid receptors mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of mu-opioid receptors with galanin Gal1 receptors, rendering a profound decrease in the potency of methadone. This was explained by methadone's weaker proficiency to activate the dopaminergic system as compared to morphine and predicted a dissociation of therapeutic versus euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-report of "high" in methadone-maintained patients. These results suggest that mu-opioid-Gal1 receptor heteromers mediate the dopaminergic effects of opioids that may lead to a lower addictive liability of opioids with selective low potency for the mu-opioid-Gal1 receptor heteromer, exemplified by methadone.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Identifying non-addictive opioid medications is a high priority in medical sciences, but mu-opioid receptors mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of mu-opioid receptors with galanin Gal1 receptors, rendering a profound decrease in the potency of methadone. This was explained by methadone's weaker proficiency to activate the dopaminergic system as compared to morphine and predicted a dissociation of therapeutic versus euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-report of "high" in methadone-maintained patients. These results suggest that mu-opioid-Gal1 receptor heteromers mediate the dopaminergic effects of opioids that may lead to a lower addictive liability of opioids with selective low potency for the mu-opioid-Gal1 receptor heteromer, exemplified by methadone.
2018
Navarro, Gemma; Cordomi, Arnau; Casado-Anguera, Veronica; Moreno, Estefania; Cai, Ning-Sheng; Cortes, Antoni; Canela, Enric I; Dessauer, Carmen W; Casado, Vicent; Pardo, Leonardo; Lluis, Carme; Ferre, Sergi
Evidence for functional pre-coupled complexes of receptor heteromers and adenylyl cyclase. Journal Article
In: Nat Commun, vol. 9, no. 1, pp. 1242, 2018, ISSN: 2041-1723 (Electronic); 2041-1723 (Linking).
@article{Navarro:2018aac,
title = {Evidence for functional pre-coupled complexes of receptor heteromers and adenylyl cyclase.},
author = {Gemma Navarro and Arnau Cordomi and Veronica Casado-Anguera and Estefania Moreno and Ning-Sheng Cai and Antoni Cortes and Enric I Canela and Carmen W Dessauer and Vicent Casado and Leonardo Pardo and Carme Lluis and Sergi Ferre},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29593213},
doi = {10.1038/s41467-018-03522-3},
issn = {2041-1723 (Electronic); 2041-1723 (Linking)},
year = {2018},
date = {2018-03-28},
journal = {Nat Commun},
volume = {9},
number = {1},
pages = {1242},
address = {Department of Biochemistry and Physiology of the Faculty of Pharmacy of the University of Barcelona, 08028, Barcelona, Spain.},
abstract = {G protein-coupled receptors (GPCRs), G proteins and adenylyl cyclase (AC) comprise one of the most studied transmembrane cell signaling pathways. However, it is unknown whether the ligand-dependent interactions between these signaling molecules are based on random collisions or the rearrangement of pre-coupled elements in a macromolecular complex. Furthermore, it remains controversial whether a GPCR homodimer coupled to a single heterotrimeric G protein constitutes a common functional unit. Using a peptide-based approach, we here report evidence for the existence of functional pre-coupled complexes of heteromers of adenosine A2A receptor and dopamine D2 receptor homodimers coupled to their cognate Gs and Gi proteins and to subtype 5 AC. We also demonstrate that this macromolecular complex provides the necessary frame for the canonical Gs-Gi interactions at the AC level, sustaining the ability of a Gi-coupled GPCR to counteract AC activation mediated by a Gs-coupled GPCR.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
G protein-coupled receptors (GPCRs), G proteins and adenylyl cyclase (AC) comprise one of the most studied transmembrane cell signaling pathways. However, it is unknown whether the ligand-dependent interactions between these signaling molecules are based on random collisions or the rearrangement of pre-coupled elements in a macromolecular complex. Furthermore, it remains controversial whether a GPCR homodimer coupled to a single heterotrimeric G protein constitutes a common functional unit. Using a peptide-based approach, we here report evidence for the existence of functional pre-coupled complexes of heteromers of adenosine A2A receptor and dopamine D2 receptor homodimers coupled to their cognate Gs and Gi proteins and to subtype 5 AC. We also demonstrate that this macromolecular complex provides the necessary frame for the canonical Gs-Gi interactions at the AC level, sustaining the ability of a Gi-coupled GPCR to counteract AC activation mediated by a Gs-coupled GPCR.
2017
Yepes, Gabriel; Guitart, Xavier; Rea, William; Newman, Amy Hauck; Allen, Richard P; Earley, Christopher J; Quiroz, Cesar; Ferre, Sergi
Targeting hypersensitive corticostriatal terminals in restless legs syndrome. Journal Article
In: Ann Neurol, vol. 82, no. 6, pp. 951–960, 2017, ISSN: 1531-8249 (Electronic); 0364-5134 (Linking).
@article{Yepes:2017aa,
title = {Targeting hypersensitive corticostriatal terminals in restless legs syndrome.},
author = {Gabriel Yepes and Xavier Guitart and William Rea and Amy Hauck Newman and Richard P Allen and Christopher J Earley and Cesar Quiroz and Sergi Ferre},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29171915},
doi = {10.1002/ana.25104},
issn = {1531-8249 (Electronic); 0364-5134 (Linking)},
year = {2017},
date = {2017-12-01},
urldate = {2017-12-01},
journal = {Ann Neurol},
volume = {82},
number = {6},
pages = {951--960},
address = {Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD.},
abstract = {OBJECTIVE: The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic model of restless legs syndrome (RLS). The second aim was to determine whether these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and alpha2 delta ligands (gabapentin). METHODS: A recently introduced in vivo optogenetic-microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light-induced stimulation of corticostriatal glutamatergic terminals. The method also allows analysis of the effect of local perfusion of compounds within the same area being sampled for glutamate. RESULTS: BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole, and gabapentin, which significantly counteracted optogenetically induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D4 and D2 receptor subtypes in the effects of pramipexole. INTERPRETATION: Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with fewer secondary effects. Ann Neurol 2017;82:951-960.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE: The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic model of restless legs syndrome (RLS). The second aim was to determine whether these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and alpha2 delta ligands (gabapentin). METHODS: A recently introduced in vivo optogenetic-microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light-induced stimulation of corticostriatal glutamatergic terminals. The method also allows analysis of the effect of local perfusion of compounds within the same area being sampled for glutamate. RESULTS: BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole, and gabapentin, which significantly counteracted optogenetically induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D4 and D2 receptor subtypes in the effects of pramipexole. INTERPRETATION: Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with fewer secondary effects. Ann Neurol 2017;82:951-960.
Moreno, Estefania; Quiroz, Cesar; Rea, William; Cai, Ning-Sheng; Mallol, Josefa; Cortes, Antoni; Lluis, Carme; Canela, Enric I; Casado, Vicent; Ferré, Sergi
Functional mu-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area. Journal Article
In: J Neurosci, vol. 37, no. 5, pp. 1176–1186, 2017, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Moreno2017,
title = {Functional mu-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area.},
author = {Estefania Moreno and Cesar Quiroz and William Rea and Ning-Sheng Cai and Josefa Mallol and Antoni Cortes and Carme Lluis and Enric I Canela and Vicent Casado and Sergi Ferré},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28007761},
doi = {10.1523/JNEUROSCI.2442-16.2016},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2017},
date = {2017-02-01},
journal = {J Neurosci},
volume = {37},
number = {5},
pages = {1176--1186},
address = {Center for Biomedical Research in Neurodegenerative Diseases Network and.},
abstract = {The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of mu-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. SIGNIFICANCE STATEMENT: The mu-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of mu-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. SIGNIFICANCE STATEMENT: The mu-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.
Bonaventura, Jordi; Quiroz, Cesar; Cai, Ning-Sheng; Rubinstein, Marcelo; Tanda, Gianluigi; Ferre, Sergi
Key role of the dopamine D4 receptor in the modulation of corticostriatal glutamatergic neurotransmission. Journal Article
In: Sci Adv, vol. 3, no. 1, pp. e1601631, 2017, ISSN: 2375-2548 (Electronic); 2375-2548 (Linking).
@article{Bonaventura2017,
title = {Key role of the dopamine D_{4} receptor in the modulation of corticostriatal glutamatergic neurotransmission.},
author = {Jordi Bonaventura and Cesar Quiroz and Ning-Sheng Cai and Marcelo Rubinstein and Gianluigi Tanda and Sergi Ferre},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28097219},
doi = {10.1126/sciadv.1601631},
issn = {2375-2548 (Electronic); 2375-2548 (Linking)},
year = {2017},
date = {2017-01-01},
journal = {Sci Adv},
volume = {3},
number = {1},
pages = {e1601631},
address = {Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural research Program, National Institutes of Health, Baltimore, MD 21224, USA.},
abstract = {Polymorphic variants of the dopamine D4 receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D4 receptor and the functional differences of the products of DRD4 polymorphic variants remained enigmatic. Immunohistochemical and optogenetic-microdialysis experiments were performed in knock-in mice expressing a D4 receptor with the long intracellular domain of a human DRD4 polymorphic variant associated with attention deficit hyperactivity disorder (ADHD). When compared with the wild-type mouse D4 receptor, the expanded intracellular domain of the humanized D4 receptor conferred a gain of function, blunting methamphetamine-induced cortical activation and optogenetic and methamphetamine-induced corticostriatal glutamate release. The results demonstrate a key role of the D4 receptor in the modulation of corticostriatal glutamatergic neurotransmission. Furthermore, these data imply that enhanced D4 receptor-mediated dopaminergic control of corticostriatal transmission constitutes a vulnerability factor of ADHD and other neuropsychiatric disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Polymorphic variants of the dopamine D4 receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D4 receptor and the functional differences of the products of DRD4 polymorphic variants remained enigmatic. Immunohistochemical and optogenetic-microdialysis experiments were performed in knock-in mice expressing a D4 receptor with the long intracellular domain of a human DRD4 polymorphic variant associated with attention deficit hyperactivity disorder (ADHD). When compared with the wild-type mouse D4 receptor, the expanded intracellular domain of the humanized D4 receptor conferred a gain of function, blunting methamphetamine-induced cortical activation and optogenetic and methamphetamine-induced corticostriatal glutamate release. The results demonstrate a key role of the D4 receptor in the modulation of corticostriatal glutamatergic neurotransmission. Furthermore, these data imply that enhanced D4 receptor-mediated dopaminergic control of corticostriatal transmission constitutes a vulnerability factor of ADHD and other neuropsychiatric disorders.
2015
Ferré, Sergi
The GPCR heterotetramer: challenging classical pharmacology. Journal Article
In: Trends Pharmacol Sci, vol. 36, no. 3, pp. 145–152, 2015, ISSN: 1873-3735 (Electronic); 0165-6147 (Linking).
@article{Ferré2015,
title = {The GPCR heterotetramer: challenging classical pharmacology.},
author = {Sergi Ferré},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25704194},
doi = {10.1016/j.tips.2015.01.002},
issn = {1873-3735 (Electronic); 0165-6147 (Linking)},
year = {2015},
date = {2015-03-01},
journal = {Trends Pharmacol Sci},
volume = {36},
number = {3},
pages = {145--152},
address = {Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health (NIH), Triad Technology Building, 333 Cassell Drive, Baltimore, MD 21224, USA. Electronic address: sferre@intra.nida.nih.gov.},
abstract = {Two concepts are gaining increasing acceptance in G protein-coupled receptor (GPCR) pharmacology: (i) pre-coupling of GPCRs with their preferred signaling molecules, and (ii) GPCR oligomerization. This is begging for the introduction of new models such as GPCR oligomer-containing signaling complexes with GPCR homodimers as functional building blocks. This model favors the formation of GPCR heterotetramers - heteromers of homodimers coupled to their cognate G protein. The GPCR heterotetramer offers an optimal framework for a canonical antagonistic interaction between activated Gs and Gi proteins, which can simultaneously bind to their respective preferred receptors and to adenylyl cyclase (AC) catalytic units. This review addresses the current evidence for pre-coupling of the various specific components that provide the very elaborate signaling machinery exemplified by the Gs-Gi-AC-coupled GPCR heterotetramer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Two concepts are gaining increasing acceptance in G protein-coupled receptor (GPCR) pharmacology: (i) pre-coupling of GPCRs with their preferred signaling molecules, and (ii) GPCR oligomerization. This is begging for the introduction of new models such as GPCR oligomer-containing signaling complexes with GPCR homodimers as functional building blocks. This model favors the formation of GPCR heterotetramers - heteromers of homodimers coupled to their cognate G protein. The GPCR heterotetramer offers an optimal framework for a canonical antagonistic interaction between activated Gs and Gi proteins, which can simultaneously bind to their respective preferred receptors and to adenylyl cyclase (AC) catalytic units. This review addresses the current evidence for pre-coupling of the various specific components that provide the very elaborate signaling machinery exemplified by the Gs-Gi-AC-coupled GPCR heterotetramer.
2014
Belcher, Annabelle M; Volkow, Nora D; Moeller, Gerard F; Ferré, Sergi
Personality traits and vulnerability or resilience to substance use disorders. Journal Article
In: Trends Cogn Sci, vol. 18, no. 4, pp. 211–217, 2014, ISSN: 1879-307X (Electronic); 1364-6613 (Linking).
@article{Belcher2014,
title = {Personality traits and vulnerability or resilience to substance use disorders.},
author = {Annabelle M Belcher and Nora D Volkow and Gerard F Moeller and Sergi Ferré},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24612993},
doi = {10.1016/j.tics.2014.01.010},
issn = {1879-307X (Electronic); 1364-6613 (Linking)},
year = {2014},
date = {2014-04-01},
journal = {Trends Cogn Sci},
volume = {18},
number = {4},
pages = {211--217},
address = {National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.},
abstract = {Clear evidence supports a genetic basis for substance use disorders (SUD). Yet, the search to identify individual gene contributions to SUD has been unsuccessful. Here, we argue for the study of endophenotypes within the frame of individual differences, and identify three high-order personality traits that are tied to specific brain systems and genes, and that offer a tractable approach to studying SUD. These personality traits, and the genes that moderate them, interact dynamically with the environment and with the drugs themselves to determine ultimately an individual's vulnerability or resilience to developing SUD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Clear evidence supports a genetic basis for substance use disorders (SUD). Yet, the search to identify individual gene contributions to SUD has been unsuccessful. Here, we argue for the study of endophenotypes within the frame of individual differences, and identify three high-order personality traits that are tied to specific brain systems and genes, and that offer a tractable approach to studying SUD. These personality traits, and the genes that moderate them, interact dynamically with the environment and with the drugs themselves to determine ultimately an individual's vulnerability or resilience to developing SUD.
Ferré, Sergi; Casado, Vicent; Devi, Lakshmi A; Filizola, Marta; Jockers, Ralf; Lohse, Martin J; Milligan, Graeme; Pin, Jean-Philippe; Guitart, Xavier
G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Journal Article
In: Pharmacol Rev, vol. 66, no. 2, pp. 413–434, 2014, ISSN: 1521-0081 (Electronic); 0031-6997 (Linking).
@article{Ferre2014,
title = {G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives.},
author = {Sergi Ferré and Vicent Casado and Lakshmi A Devi and Marta Filizola and Ralf Jockers and Martin J Lohse and Graeme Milligan and Jean-Philippe Pin and Xavier Guitart},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24515647},
doi = {10.1124/pr.113.008052},
issn = {1521-0081 (Electronic); 0031-6997 (Linking)},
year = {2014},
date = {2014-02-11},
journal = {Pharmacol Rev},
volume = {66},
number = {2},
pages = {413--434},
address = {Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes on Drug Abuse, Department of Health and Human Services, 333 Cassell Drive, Baltimore, Maryland 21224. sferre@intra.nida.nih.gov.},
abstract = {Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seem to apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and high-throughput screening approaches to the discovery of receptor-heteromer selective compounds.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seem to apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and high-throughput screening approaches to the discovery of receptor-heteromer selective compounds.
