Receptor⁻Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment

• Published in: Molecules (Basel, Switzerland) Switzerland), 2018, Vol.23 (6), p.1341
• Main Authors: Borroto-Escuela, Dasiel O, Narváez, Manuel, Ambrogini, Patrizia, Ferraro, Luca, Brito, Ismel, Romero-Fernandez, Wilber, Andrade-Talavera, Yuniesky, Flores-Burgess, Antonio, Millon, Carmelo, Gago, Belen, Narvaez, Jose Angel, Odagaki, Yuji, Palkovits, Miklos, Diaz-Cabiale, Zaida, Fuxe, Kjell
• Format: Article
• Language: English
• Subjects: Antidepressants; Brain research; depression; fibroblast growth factor receptor; Fibroblast growth factor receptor 1; Fluoxetine; G protein-coupled receptors; Galanin; heteroreceptor complexes; Hippocampal plasticity; Hippocampus; Ligands; Medicin och hälsovetenskap; Mental depression; Neurons; Neuroplasticity; Neurosciences; oligomerization; Potassium channels (inwardly-rectifying); Proteins; Rats; receptor tyrosine kinase; receptor-receptor interactions; Review; Serotonin; serotonin 5-HT1A receptor; Serotonin S1 receptors; Serotonin S2 receptors
• ISSN: 1420-3049; 1431-5157; 1420-3049
• DOI: 10.3390/molecules23061341

Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term "heteroreceptor complexes" was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A⁻FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A⁻FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A⁻5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1⁻15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1⁻GalR2⁻5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.