Editorial (Thematic Issue: Understanding the Role of Heteroreceptor Complexes in the Central Nervous System)
Abstract
This special issue is based on a mini-symposium in the area of neurosciences with the title "Understanding the role of heteroreceptor complexes in the central nervous system" held at the Nobel Forum, Karolinska Institutet on December 17th, 2012, organized by Kjell Fuxe, Dasiel O. Borroto-Escuela and Luigi F. Agnati. It consists of seven mini-reviews in the field receptor heteromers. The early work on negative cooperativity and neuropeptide-monoamine receptor-receptor interactions in the central nervous system gave the first indications of the existence of homomers and heteromers of G-protein coupled receptors (GPCR), respectively, and the GPCR field began to expand from monomers into dimers and receptor mosaics (higher-order dimers). It was underlined that the existence of receptor heteromers with allosteric receptor-receptor interactions increases the diversity and bias of GPCR recognition and signalling. The molecular phenomenon of allosteric receptor-receptor interactions is proposed to give a better understanding of brain function through molecular integration of signals. An alteration in specific receptor-receptor interactions is in fact considered to play a role in pathogenic mechanisms leading to several diseases, inter alia Parkinson's disease, hypertension, schizophrenia, addiction and depression. It is a new principle in molecular medicine. Therefore, pharmacological targeting of receptor-receptor interactions in heteromers will become an important area for developing more selective drugs with reduced side-effects including heterobivalent compounds and optimal types of combined treatments. In other words , it will lead to novel strategies for treatment, and finally novel drugs for treatment of disease. The first mini-review by Dr. Tena-Campus and colleagues introduces the field of GPCR oligomerization as emerging signalling units with new opportunities for drug design and discusses the technologies involved for detection of receptor heteromers. Then the issue moves into examples of receptor-receptor interactions in the DA and neuropeptide field. Dr. Van Craenenbroeck and colleagues presents an article on the role of dimerization in the biogenesis of DA D4 receptors and thus in their maturation. Dr. Zaida Diaz-Cabiale and colleagues describe the existence of galanin receptor-neuropeptide Y receptor interactions in the brain including galanin receptor-neuropeptide Y Y1 interactions in the brain stem. Indications are obtained that the receptor target for galanin fragment 1-15 is instead a GalR1-GalR2 heteromer. Then the special issue enters into the role of receptor-receptor interactions in putative striatal GPCR heteromers in Parkinson's disease and schizophrenia. Dr. Beggiato and colleagues discuss the role of antagonistic adenosine A2A-D2 receptorreceptor interactions in the striato-pallidal GABA neurons and their relevance for treatment of Parkinson's disease. They give the rationale for the introduction of A2A receptor antagonists in clinical trials in this disease based on these antagonistic receptor- receptor interactions which become even more strongly developed in animal models of Parkinson's disease. Dr. Luca Ferraro and colleagues instead discuss in detail the antagonistic Neurotensin NTS1-dopamine D2 receptor-receptor interactions in putative receptor heteromers in the dorsal and ventral striatum. Their involvement in striato-pallidal GABA and mesocorticolimbic DA communication is discussed with focus on their relevance for Parkinson's disease, schizophrenia and their treatments. Dr. Di Liberto and colleagues deal with the role of receptor-receptor interactions in brain trophism and plasticity with focus on interactions between G protein-coupled receptor-Receptor Tyrosine Kinase, specially the cholinergic and fibroblast growth factor receptor 1 (FGFR1). mAChR-FGFR1 interactions are indicated leading to transactivation of FGFR1 with potential relevance for cognition. Luigi Agnati and colleagues in the last paper of this special issue suggest a unified perspective for integrative brain actions through " neurosemeiotics" and " free energy minimization". Especially the Bio-semeiotics concept of "adaptor" may involve the receptor-receptor interactions in heteroreceptor complexes. Through such "adaptors" a code may be produced that give meaning to the sensory stimuli reaching the cortical regions of the brain . We hope the readers will find the articles in this special issue of interest and may give some inspiration to enter this exciting field of receptor research in the CNS which opens up a novel understanding of the molecular events that may lead to neurological and mental diseases and offer novel strategies for their treatments. The editors are grateful to the authors for their fine contributions to this special issue.
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GPCR heteroreceptor complexes exert allosteric receptor-receptor interactions that modulate the recognition, signaling, and trafficking of the participating receptor protomers.
“These complexes exert allosteric receptor–receptor interactions that modulate the recognition, signaling, and trafficking of the participating receptor protomers, thereby influencing other associated proteins (Fuxe et al., 2010; Borroto-Escuela et al., 2014; Fuxe et al., 2014; Borroto-Escuela et al., 2015b; Fuxe and Borroto-Escuela, 2016; Borroto-Escuela et al., 2017a).”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as Fuxe et al., 2014
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Dopamine in Health and Disease: Much More Than a Neurotransmitter
Franco, R., Reyes‐Resina, I., & Navarro, G. (2021) · Biomedicines · doi:10.3390/biomedicines9020109 · Cited by 207 · see citing works
Borroto‐Escuela, D. O., Carlsson, J., Ambrogini, P., Narváez, M., Wydra, K., Tarakanov, A. O., Li, X., Millón, C., Ferraro, L., Cuppini, R., et al. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00037 · Cited by 375 · see citing works
“The allosteric interactions in such dynamic higher order receptor complexes take place in an orchestrated spatio-temporal fashion and participate in learning and formation of molecular engrams for short and long term memory (Fuxe et al., 2014b; Borroto-Escuela et al., 2015a).”
BackgroundMethodInfluentialSelf-citationLiberto, V. D., Mudò, G., & Belluardo, N. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.11.018 · Cited by 83 · see citing works
García‐Gutiérrez, M. S., Navarrete, F., Navarro, G., Reyes‐Resina, I., Franco, R., Lanciego, J. L., Giner, S., & Manzanares, J. (2018) · Neurotherapeutics · doi:10.1007/s13311-018-0610-y · Cited by 65 · see citing works
Borroto‐Escuela, D. O., Narváez, M., Ambrogini, P., Ferraro, L., Brito, I., Romero‐Fernandez, W., Andrade‐Talavera, Y., Flores‐Burgess, A., Millón, C., Gago, B., et al. (2018) · Molecules · doi:10.3390/molecules23061341 · Cited by 50 · see citing works
Self-citationBorroto‐Escuela, D. O., & Fuxé, K. (2019) · Journal of Neural Transmission · doi:10.1007/s00702-019-01969-2 · Cited by 48 · see citing works
Self-citationConstantin, S., & Wray, S. (2016) · Endocrinology · doi:10.1210/en.2016-1064 · Cited by 42 · see citing works
Glutamate heteroreceptor complexes in the brain
Borroto‐Escuela, D. O., Tarakanov, A. O., Brito, I., & Fuxé, K. (2018) · Pharmacological Reports · doi:10.1016/j.pharep.2018.04.002 · Cited by 42 · see citing works
Self-citationBorroto‐Escuela, D. O., Hagman, B., Woolfenden, M., Pinton, L., Jimenez‐Beristain, A., Oflijan, J., Narváez, M., Palma, M. D., Feltmann, K., Sartini, S., et al. (2016) · Neuromethods · doi:10.1007/978-1-4939-3064-7_9 · Cited by 45 · see citing works
Self-citationBorroto‐Escuela, D. O., & Fuxé, K. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00230 · Cited by 39 · see citing works
“Upon a change in the release pattern of transmitters in the synapse, learning of this new pattern will take place in the postsynaptic membrane through a reorganization of the homo and heteroreceptor complexes (Fuxe et al., 2014c; Borroto-Escuela et al., 2015a).”
BackgroundMethodInfluentialSelf-citationBorroto-Escuela, D. O., Cuesta-Marti, C., Lopez-Salas, A., Chruścicka-Smaga, B., Crespo-Ramírez, M., Tesoro-Cruz, E., Palacios-Lagunas, D. A., Perez de la Mora, M., Schellekens, H., & Fuxe, K. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1055344 · Cited by 38 · see citing works
Self-citationAuvin, S., Galanopoulou, A. S., Moshé, S. L., Potschka, H., Rocha, L., Walker, M. C., & the TASK1 workgroup on drug‐resistant epilepsy of the ILAE/AES Joint Translational Task Force (2023) · Epilepsia · doi:10.1111/epi.17751 · Cited by 39 · see citing works
“82 Mosaics result from the physical interactions at 40 nm between receptors and ion channels.”
BackgroundHurdles in Basic Science Translation
Perry, C. J., & Lawrence, A. J. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00478 · Cited by 36 · see citing works
“Indeed receptors may be heterodimers or even larger mosaics made up of different receptor type subunits (Fuxe et al., 2014).”
BackgroundKautzky, A., James, G. M., Philippe, C., Baldinger, P., Kraus, C., Kranz, G. S., Vanicek, T., Gryglewski, G., Wadsak, W., Mitterhauser, M., et al. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.108 · Cited by 35 · see citing works
Borroto‐Escuela, D. O., DuPont, C. M., Li, X., Savelli, D., Lattanzi, D., Srivastava, I., Narváez, M., Palma, M. D., Barbieri, E., Andrade‐Talavera, Y., et al. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00309 · Cited by 33 · see citing works
“This allosteric receptor mechanism may also exist in the postjunctional FGFR1-5-HT1A heteroreceptor complexes located on hippocampal pyramidal neurons (Borroto-Escuela et al., 2012, 2015a,b; Fuxe et al., 2014).”
BackgroundSelf-citationOn the Role of the Balance of GPCR Homo/ Heteroreceptor Complexes in the Brain
Borroto-Escuela, D., Brito, I., Palma, M. D., Jimenez‐Beristain, A., Narváez, M., Corrales, F., Pita-Rodríguez, M., Sartini, S., Ambrogini, P., Lattanzi, D., et al. (2015) · Journal of Advanced Neuroscience Research · doi:10.15379/2409-3564.2015.02.01.5 · Cited by 27 · see citing works
Self-citationAdenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine
Wydra, K., Gawliński, D., Gawlińska, K., Frankowska, M., Borroto‐Escuela, D. O., Fuxé, K., & Filip, M. (2020) · Cells · doi:10.3390/cells9061372 · Cited by 20 · see citing works
Self-citationHernández-Mondragón, J. C., Hernández-Hernández, D. A., Crespo-Ramírez, M., Prospero-García, O., Rocha-Arrieta, L., Fuxe, K., Borroto-Escuela, D. O., & Perez de la Mora, M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1251922 · Cited by 17 · see citing works
Self-citationUnderstanding electrical and chemical transmission in the brain
Borroto‐Escuela, D. O., Gonzalez-Cristo, E., Ochoa-Torres, V., Serra-Rojas, E. M., Ambrogini, P., Arroyo‐García, L. E., & Fuxé, K. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1398862 · Cited by 14 · see citing works
Self-citationNarváez, M., Crespo‐Ramírez, M., Fores‐Pons, R., Pita-Rodríguez, M., Ciruela, F., Filip, M., Beggiato, S., Ferraro, L., Tanganelli, S., Ambrogini, P., et al. (2021) · Neuromethods · doi:10.1007/978-1-0716-1522-5_9 · Cited by 11 · see citing works
Self-citationLubec, J., Hussein, A. M., Kalaba, P., Feyissa, D. D., Arias‐Sandoval, E., Cybulska-Kłosowicz, A., Bezu, M., Stojanovic, T., Korz, V., Maliković, J., et al. (2023) · Biomolecules · doi:10.3390/biom13030467 · Cited by 9 · see citing works
Dremencov, E., Lacinová, Ľ., Flik, G., et al. (2017) · General Physiology and Biophysics · doi:10.4149/gpb_2017039 · Cited by 9 · see citing works
Kautzky, A., James, G. M., Philippe, C., Baldinger, P., Kraus, C., Kranz, G. S., Vanicek, T., Gryglewski, G., Hartmann, A. M., Hahn, A., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-018-0308-2 · Cited by 9 · see citing works
Spulber, S. D., Conti, M., Elberling, F., Raciti, M., Borroto‐Escuela, D. O., Fuxé, K., & Ceccatelli, S. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0594-3 · Cited by 8 · see citing works
Self-citationLiu, G., Chen, X., ZHOU, W., et al. (2016) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2016.3084 · Cited by 7 · see citing works
Borroto‐Escuela, D. O., Narváez, M., Valladolid‐Acebes, I., Shumilov, K., Palma, M. D., Wydra, K., Schaefer, T., Reyes‐Resina, I., Navarro, G., Mudò, G., et al. (2018) · Neuromethods · doi:10.1007/978-1-4939-8576-0_19 · Cited by 6 · see citing works
Self-citationFlores‐Burgess, A., Millón, C., Cantero-García, N., Pineda-Gómez, J. P., Flores-Gómez, M., & Dı́az-Cabiale, Z. (2024) · Current Neuropharmacology · doi:10.2174/1570159x23666241003125019 · Cited by 3 · see citing works
Regulation of FGF2-induced proliferation by inhibitory GPCR in normal pituitary cells
Sosa, L. D. V., Picech, F., Pérez, P., Gutiérrez, S., Leal, R., Paul, A. D. D., Torres, A., & Petiti, J. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1183151 · Cited by 2 · see citing works
“In this sense, previous studies have reported that inhibitory G protein-coupled receptors (GPCR-G a i) may regulate the intracellular signaling triggered by growth factor receptors transactivation (9 – 11).”
BackgroundBrito, I., Narváez, M., Savelli, D., et al. (2018) · Neuromethods · doi:10.1007/978-1-4939-8576-0_18 · Cited by 1 · see citing works
Self-citationBorroto‐Escuela, D. O., Narváez, M., Zannoni, M., et al. (2018) · Neuromethods · doi:10.1007/978-1-4939-8985-0_10 · Cited by 1 · see citing works
Self-citationNavarro, G., Borroto‐Escuela, D. O., Fuxe, K., & Franco, R. (2018) · Springer eBooks · doi:10.1007/978-3-319-90808-3_10
Self-citationBorroto‐Escuela, D. O., de la Mora, M. P., Zoli, M., Benfenati, F., Narváez, M., Rivera, A., Dı́az-Cabiale, Z., Beggiato, S., Ferraro, L., Tanganelli, S., et al. (2018) · Neuromethods · doi:10.1007/978-1-4939-8576-0_1
Self-citationCorrales, F. (2017) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
- Authors
- Fuxe, K., Borroto-Escuela, D., Fisone, G., Agnati, L., & Tanganelli, S.
- Affiliations
- Karolinska Institutet (SE)
- Venue
- Current Protein & Peptide Science
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2014-09-16
- Volume
- 15
- Issue
- 7
- Pages
- 647-647
- ISSN
- 1389-2037 (ISSN-L)
- OpenAlex
- W2124624667
- Cited by
- 33
- References
- 0
- Citations by year
- 2024: 2 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 9 · 2017: 6 · 2016: 3 · 2015: 1
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Protein and Peptide Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Karolinska Institutet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- GPCR oligomerization, allosteric interactions, negative cooperativity, dopamine D4 receptor, galanin receptors, neuropeptide Y receptors, receptor dimerization, Parkinson's disease, schizophrenia, drug design, central nervous system
- MeSH terms
- Animals, Central Nervous System, Humans, Neurons, Neuropeptides, Parkinson Disease, Signal Transduction, Receptors, G-Protein-Coupled
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