Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia-Relevance for Mental Diseases.

Autor: Borroto-Escuela DO; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.; Department of Biomolecular Science Section of Morphology, Physiology and Environmental Biology, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, 61029 Urbino, Italy.; Facultad de Medicina, Instituto de Investigacion de Málaga, Universidad de Malaga, Campus de Teatinos s/n, 29071 Málaga, Spain., Ambrogini P; Department of Biomolecular Science Section of Morphology, Physiology and Environmental Biology, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, 61029 Urbino, Italy., Narvaez M; Facultad de Medicina, Instituto de Investigacion de Málaga, Universidad de Malaga, Campus de Teatinos s/n, 29071 Málaga, Spain., Di Liberto V; Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, 90134 Palermo, Italy., Beggiato S; Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, 66100 Chieti, Italy., Ferraro L; Department of Life Sciences and Biotechnology and LTTA Center, University of Ferrara, 44121 Ferrara, Italy., Fores-Pons R; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.; Facultad de Medicina, Instituto de Investigacion de Málaga, Universidad de Malaga, Campus de Teatinos s/n, 29071 Málaga, Spain., Alvarez-Contino JE; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.; Department of Education, School of Medicine, Villa Clara University of Medical Sciences, Polyclinic Juan Bruno Zayas, 52900 Cifuentes, Cuba., Lopez-Salas A; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.; Facultad de Medicina, Instituto de Investigacion de Málaga, Universidad de Malaga, Campus de Teatinos s/n, 29071 Málaga, Spain., Mudò G; Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, 90134 Palermo, Italy., Díaz-Cabiale Z; Facultad de Medicina, Instituto de Investigacion de Málaga, Universidad de Malaga, Campus de Teatinos s/n, 29071 Málaga, Spain., Fuxe K; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
Jazyk: angličtina
Zdroj: Cells [Cells] 2021 Jul 27; Vol. 10 (8). Date of Electronic Publication: 2021 Jul 27.
DOI: 10.3390/cells10081902
Abstrakt: 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.
Databáze: MEDLINE
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