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RESEARCH PRODUCT
Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases
Valentina Di LibertoAlexander Lopez-salasAlexander Lopez-salasLuca FerraroSarah BeggiatoDasiel O. Borroto-escuelaDasiel O. Borroto-escuelaManuel NarváezJose E. Alvarez-continoRamon Fores-ponsRamon Fores-ponsZaida Díaz-cabialePatrizia AmbroginiGiuseppa MudòKjell Fuxesubject
0301 basic medicineReviewheteroreceptor complexesTropomyosin receptor kinase BReceptor tyrosine kinasechemistry.chemical_compound0302 clinical medicineG protein-coupled receptorsserotonin receptorsReceptor Serotonin 5-HT2ABiology (General)astrogliabiologyChemistryMental DisordersBrainGeneral MedicineAntidepressive AgentsdepressionG protein-coupled receptors; astroglia; depression; heteroreceptor complexes; rapid antidepressant drugs; receptor tyrosine kinase; serotonin receptors.medicine.symptomAntipsychotic AgentsSerotonergic NeuronsSignal TransductionProto-oncogene tyrosine-protein kinase Srcserotonin receptorheteroreceptor complexeQH301-705.5Astroglia; Depression; G protein-coupled receptors; Heteroreceptor complexes; Rapid antidepressant drugs; Receptor tyrosine kinase; Serotonin receptors;Allosteric regulationserotonin receptors heteroreceptor complexes depression astroglia receptor tyrosine kinase rapid antidepressant drugs G protein-coupled receptors.depression astroglia receptor tyrosine kinase rapid antidepressant drugs G protein-coupled receptorsHeteroreceptorNO03 medical and health sciencesmedicineAnimalsHumansReceptor Fibroblast Growth Factor Type 1rapid antidepressant drugsG protein-coupled receptorReceptors Dopamine D2Dopaminergic NeuronsTyrosine phosphorylationReceptor Cross-TalkReceptor Galanin Type 1Receptor Galanin Type 2030104 developmental biologyMechanism of actionAstrocytesreceptor tyrosine kinasebiology.proteinReceptors Serotonin 5-HT1Neuroscience030217 neurology & neurosurgerydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-07-27 | Cells |