Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases
The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can...
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doaj-c4ddabb8dd704ecd8e44796b0f8407832021-08-26T13:37:01ZengMDPI AGCells2073-44092021-07-01101902190210.3390/cells10081902Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental DiseasesDasiel O. Borroto-Escuela0Patrizia Ambrogini1Manuel Narvaez2Valentina Di Liberto3Sarah Beggiato4Luca Ferraro5Ramon Fores-Pons6Jose E. Alvarez-Contino7Alexander Lopez-Salas8Giuseppa Mudò9Zaida Díaz-Cabiale10Kjell Fuxe11Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, SwedenDepartment of Biomolecular Science Section of Morphology, Physiology and Environmental Biology, Campus Scientifico Enrico Mattei, via Ca’ le Suore 2, 61029 Urbino, ItalyFacultad de Medicina, Instituto de Investigacion de Málaga, Universidad de Malaga, Campus de Teatinos s/n, 29071 Málaga, SpainDepartment of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, 90134 Palermo, ItalyDepartment of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Life Sciences and Biotechnology and LTTA Center, University of Ferrara, 44121 Ferrara, ItalyDepartment of Neuroscience, Karolinska Institutet, 171 77 Stockholm, SwedenDepartment of Neuroscience, Karolinska Institutet, 171 77 Stockholm, SwedenDepartment of Neuroscience, Karolinska Institutet, 171 77 Stockholm, SwedenDepartment of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, 90134 Palermo, ItalyFacultad de Medicina, Instituto de Investigacion de Málaga, Universidad de Malaga, Campus de Teatinos s/n, 29071 Málaga, SpainDepartment of Neuroscience, Karolinska Institutet, 171 77 Stockholm, SwedenThe heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.https://www.mdpi.com/2073-4409/10/8/1902serotonin receptorsheteroreceptor complexesdepressionastrogliareceptor tyrosine kinaserapid antidepressant drugs |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dasiel O. Borroto-Escuela Patrizia Ambrogini Manuel Narvaez Valentina Di Liberto Sarah Beggiato Luca Ferraro Ramon Fores-Pons Jose E. Alvarez-Contino Alexander Lopez-Salas Giuseppa Mudò Zaida Díaz-Cabiale Kjell Fuxe |
spellingShingle |
Dasiel O. Borroto-Escuela Patrizia Ambrogini Manuel Narvaez Valentina Di Liberto Sarah Beggiato Luca Ferraro Ramon Fores-Pons Jose E. Alvarez-Contino Alexander Lopez-Salas Giuseppa Mudò Zaida Díaz-Cabiale Kjell Fuxe Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases Cells serotonin receptors heteroreceptor complexes depression astroglia receptor tyrosine kinase rapid antidepressant drugs |
author_facet |
Dasiel O. Borroto-Escuela Patrizia Ambrogini Manuel Narvaez Valentina Di Liberto Sarah Beggiato Luca Ferraro Ramon Fores-Pons Jose E. Alvarez-Contino Alexander Lopez-Salas Giuseppa Mudò Zaida Díaz-Cabiale Kjell Fuxe |
author_sort |
Dasiel O. Borroto-Escuela |
title |
Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases |
title_short |
Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases |
title_full |
Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases |
title_fullStr |
Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases |
title_full_unstemmed |
Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases |
title_sort |
serotonin heteroreceptor complexes and their integration of signals in neurons and astroglia—relevance for mental diseases |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2021-07-01 |
description |
The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder. |
topic |
serotonin receptors heteroreceptor complexes depression astroglia receptor tyrosine kinase rapid antidepressant drugs |
url |
https://www.mdpi.com/2073-4409/10/8/1902 |
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