
Contact
Triad Technology Center333 Cassell Drive
Room 4500
Baltimore, MD 21224
Email: ncai@intra.nida.nih.gov
Education
Ph.D. - Molecular Pharmacology at Gottingen University, Gottingen, Germany & Academy of Military Medical Sciences, Beijing, P.R. China
M.S. - Biotechnology at Advanced Academic Programs, Johns Hopkins University, Maryland
M.S. - Biochemical Pharmacology Academy of Military Medical Sciences, Beijing, P.R. China
M.D. - Medicine at Third Military Medical College, Shanghai, P.R. China
Publications
Selected Publications
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}
}
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
Guitart, Xavier; Moreno, Estefanía; Rea, William; Sánchez-Soto, Marta; Cai, Ning-Sheng; Quiroz, César; Kumar, Vivek; Bourque, Liam; Cortés, Antoni; Canela, Enric I; Bishop, Christopher; Newman, Amy Hauck; Casadó, Vicent; Ferré, Sergi
Biased G Protein-Independent Signaling of Dopamine D-D Receptor Heteromers in the Nucleus Accumbens Journal Article
In: Mol Neurobiol, vol. 56, no. 10, pp. 6756–6769, 2019, ISSN: 1559-1182.
@article{pmid30919214,
title = {Biased G Protein-Independent Signaling of Dopamine D-D Receptor Heteromers in the Nucleus Accumbens},
author = {Xavier Guitart and Estefanía Moreno and William Rea and Marta Sánchez-Soto and Ning-Sheng Cai and César Quiroz and Vivek Kumar and Liam Bourque and Antoni Cortés and Enric I Canela and Christopher Bishop and Amy Hauck Newman and Vicent Casadó and Sergi Ferré},
url = {https://pubmed.ncbi.nlm.nih.gov/30919214/},
doi = {10.1007/s12035-019-1564-8},
issn = {1559-1182},
year = {2019},
date = {2019-10-01},
urldate = {2019-10-01},
journal = {Mol Neurobiol},
volume = {56},
number = {10},
pages = {6756--6769},
abstract = {Several studies found in vitro evidence for heteromerization of dopamine D receptors (D1R) and D receptors (D3R), and it has been postulated that functional D1R-D3R heteromers that are normally present in the ventral striatum mediate synergistic locomotor-activating effects of D1R and D3R agonists in rodents. Based also on results obtained in vitro, with mammalian transfected cells, it has been hypothesized that those behavioral effects depend on a D1R-D3R heteromer-mediated G protein-independent signaling. Here, we demonstrate the presence on D1R-D3R heteromers in the mouse ventral striatum by using a synthetic peptide that selectively destabilizes D1R-D3R heteromers. Parallel locomotor activity and ex vivo experiments in reserpinized mice and in vitro experiments in D1R-D3R mammalian transfected cells were performed to dissect the signaling mechanisms of D1R-D3R heteromers. Co-administration of D1R and D3R agonists in reserpinized mice produced synergistic locomotor activation and a selective synergistic AKT phosphorylation in the most ventromedial region of the striatum in the shell of the nucleus accumbens. Application of the destabilizing peptide in transfected cells and in the shell of the nucleus accumbens allowed demonstrating that both in vitro and in vivo co-activation of D3R induces a switch from G protein-dependent to G protein-independent D1R-mediated signaling determined by D1R-D3R heteromerization. The results therefore demonstrate that a biased G protein-independent signaling of D1R-D3R heteromers localized in the shell of the nucleus accumbens mediate the locomotor synergistic effects of D1R and D3R agonists in reserpinized mice.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sánchez-Soto, Marta; Yano, Hideaki; Cai, Ning-Sheng; Casadó-Anguera, Verònica; Moreno, Estefanía; Casadó, Vicent; Ferré, Sergi
Revisiting the Functional Role of Dopamine D Receptor Gene Polymorphisms: Heteromerization-Dependent Gain of Function of the D Receptor Variant Journal Article
In: Mol Neurobiol, vol. 56, no. 7, pp. 4778–4785, 2019, ISSN: 1559-1182.
@article{pmid30387076,
title = {Revisiting the Functional Role of Dopamine D Receptor Gene Polymorphisms: Heteromerization-Dependent Gain of Function of the D Receptor Variant},
author = {Marta Sánchez-Soto and Hideaki Yano and Ning-Sheng Cai and Verònica Casadó-Anguera and Estefanía Moreno and Vicent Casadó and Sergi Ferré},
url = {https://pubmed.ncbi.nlm.nih.gov/30387076/},
doi = {10.1007/s12035-018-1413-1},
issn = {1559-1182},
year = {2019},
date = {2019-07-01},
urldate = {2019-07-01},
journal = {Mol Neurobiol},
volume = {56},
number = {7},
pages = {4778--4785},
abstract = {The two most common polymorphisms of the human DRD4 gene encode a dopamine D receptor (D4R) with four or seven repeats of a proline-rich sequence of 16 amino acids (D4.4R or D4.7R). Although the seven-repeat polymorphism has been repeatedly associated with attention-deficit hyperactivity disorder and substance use disorders, the differential functional properties between D4.4R and D4.7R remained enigmatic until recent electrophysiological and optogenetic-microdialysis experiments indicated a gain of function of D4.7R. Since no clear differences in the biochemical properties of individual D4.4R and D4.7R have been reported, it was previously suggested that those differences emerge upon heteromerization with dopamine D receptor (D2R), which co-localizes with D4R in the brain. However, contrary to a gain of function, experiments in mammalian transfected cells suggested that heteromerization with D2R results in lower MAPK signaling by D4.7R as compared to D4.4R. In the present study, we readdressed the question of functional differences of D4.4R and D4.7R forming homomers or heteromers with the short isoform of D2R (D2SR), using a functional bioluminescence resonance energy transfer (BRET) assay that allows the measurement of ligand-induced changes in the interaction between G protein-coupled receptors (GPCRs) forming homomers or heteromers with their cognate G protein. Significant functional and pharmacological differences between D4.4R and D4.7R were only evident upon heteromerization with the short isoform of D2R (D2SR). The most dramatic finding was a significant increase and decrease in the constitutive activity of D2S upon heteromerization with D4.7R and D4.4R, respectively, providing the first clear mechanism for a functional difference between both products of polymorphic variants and for a gain of function of the D4.7R.},
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Cai, Ning-Sheng; Quiroz, César; 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, Estefanía; Casadó-Anguera, Verònica; Greenblatt, Aaron D; Jacobson, Arthur E; Rice, Kenner C; Casadó, Vicent; Newman, Amy Hauck; Winkelman, John W; Michaelides, Michael; Weintraub, Eric; Volkow, Nora D; Belcher, Annabelle M; Ferré, Sergi
Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids Journal Article
In: J Clin Invest, vol. 129, no. 7, pp. 2730–2744, 2019, ISSN: 1558-8238.
@article{pmid30913037,
title = {Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids},
author = {Ning-Sheng Cai and César 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 Estefanía Moreno and Verònica Casadó-Anguera and Aaron D Greenblatt and Arthur E Jacobson and Kenner C Rice and Vicent Casadó and Amy Hauck Newman and John W Winkelman and Michael Michaelides and Eric Weintraub and Nora D Volkow and Annabelle M Belcher and Sergi Ferré},
url = {https://pubmed.ncbi.nlm.nih.gov/30913037/},
doi = {10.1172/JCI126912},
issn = {1558-8238},
year = {2019},
date = {2019-01-01},
urldate = {2019-01-01},
journal = {J Clin Invest},
volume = {129},
number = {7},
pages = {2730--2744},
abstract = {Identifying non-addictive opioid medications is a high priority in medical sciences, but μ-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 μ-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 μ-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 μ-opioid-Gal1 receptor heteromer, exemplified by methadone.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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}
}
Yano, Hideaki; Cai, Ning-Sheng; Xu, Min; Verma, Ravi Kumar; Rea, William; Hoffman, Alexander F; Shi, Lei; Javitch, Jonathan A; Bonci, Antonello; Ferre, Sergi
Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor. Journal Article
In: Nat Commun, vol. 9, no. 1, pp. 486, 2018, ISSN: 2041-1723 (Electronic); 2041-1723 (Linking).
@article{Yano:2018aa,
title = {Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor.},
author = {Hideaki Yano and Ning-Sheng Cai and Min Xu and Ravi Kumar Verma and William Rea and Alexander F Hoffman and Lei Shi and Jonathan A Javitch and Antonello Bonci and Sergi Ferre},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29402888},
doi = {10.1038/s41467-017-02606-w},
issn = {2041-1723 (Electronic); 2041-1723 (Linking)},
year = {2018},
date = {2018-02-05},
journal = {Nat Commun},
volume = {9},
number = {1},
pages = {486},
address = {National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. hideaki.yano@nih.gov.},
abstract = {The two highly homologous subtypes of stimulatory G proteins Galphas (Gs) and Galphaolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D1 receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction.},
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2017
Moreno, Estefania; Quiroz, Cesar; Rea, William; Cai, Ning-Sheng; Mallol, Josefa; Cortes, Antoni; Lluis, Carme; Canela, Enric I; Casado, Vicent; Ferre, Sergi
Functional μ-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{Moreno:2017aa,
title = {Functional μ-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 Ferre},
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 = {2017-02-03},
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}
}
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}
}
