RT Journal Article
T1 Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia-Relevance for Mental Diseases.
A1 Borroto-Escuela, Dasiel O
A1 Ambrogini, Patrizia
A1 Narvaez, Manuel
A1 Di Liberto, Valentina
A1 Beggiato, Sarah
A1 Ferraro, Luca
A1 Fores-Pons, Ramon
A1 Alvarez-Contino, Jose E
A1 Lopez-Salas, Alexander
A1 Mudò, Giuseppa
A1 Díaz-Cabiale, Zaida
A1 Fuxe, Kjell
K1 G protein-coupled receptors
K1 astroglia
K1 depression
K1 heteroreceptor complexes
K1 rapid antidepressant drugs
K1 receptor tyrosine kinase
K1 serotonin receptors
AB 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.
YR 2021
FD 2021-07-27
LK http://hdl.handle.net/10668/18431
UL http://hdl.handle.net/10668/18431
LA en
DS RISalud
RD Apr 6, 2025