Receptor–receptor interactions in multiple 5-HT1A heteroreceptor complexes in raphe-hippocampal 5-HT transmission and their relevance for depression and its treatment

Dasiel O. Borroto-Escuela, Manuel Narváez, Patrizia Ambrogini, Luca Ferraro, Ismel Brito, Wilber Romero-Fernandez, Yuniesky Andrade-Talavera, Antonio Flores-Burgess, Carmelo Millon, Belen Gago, Jose Angel Narvaez, Yuji Odagaki, Miklos Palkovits, Zaida Diaz-Cabiale, Kjell Fuxe

Research output: Contribution to journalReview article

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number1341
JournalMolecules
Volume23
Issue number6
DOIs
Publication statusPublished - 2018

Keywords

  • Depression
  • Fibroblast growth factor receptor
  • G protein-coupled receptors
  • Galanin
  • Heteroreceptor complexes
  • Oligomerization
  • Receptor tyrosine kinase
  • Receptor-receptor interactions
  • Serotonin 5-HT1A receptor

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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  • Cite this

    Borroto-Escuela, D. O., Narváez, M., Ambrogini, P., Ferraro, L., Brito, I., Romero-Fernandez, W., Andrade-Talavera, Y., Flores-Burgess, A., Millon, C., Gago, B., Narvaez, J. A., Odagaki, Y., Palkovits, M., Diaz-Cabiale, Z., & Fuxe, K. (2018). Receptor–receptor interactions in multiple 5-HT1A heteroreceptor complexes in raphe-hippocampal 5-HT transmission and their relevance for depression and its treatment. Molecules, 23(6), [1341]. https://doi.org/10.3390/molecules23061341