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

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

doi:10.3390/molecules23061341

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.

Highlights

In membrane preparations of various central nervous system (CNS) regions, it was found in the1980s that neuropeptides such as CCK8 and neurotensin could modulate the binding characteristics via their receptors, especially the affinity of the monoamine receptors in a receptor subtype-specific way [1,2,3]
In a recent paper [11], it was found in control Sprague Dawley rats that FGF2 and a FGFR1 receptor agonist Sun-11602 diminished the currents over the G protein-coupled inwardly rectifying potassium channels (GIRK) produced by a 5-HT1A receptor agonist in pyramidal nerve cells of the
The reason for this is unclear, because there was an indication for a possible increase of the 5-HT1A–FGFR1 autoreceptor complexes in the dorsal raphe versus the control rat

Summary

Introduction

In membrane preparations of various central nervous system (CNS) regions, it was found in the. The allosteric receptor–receptor interactions in heteroreceptor complexes give diversity and bias to the receptor protomers due to conformational changes in discrete receptor domains altering receptor protomer function and pharmacology [8,9]. 5-HT subtype-selective antagonists or agonists can be used, inter alia, to enhance the antidepressant actions of SSRIs [29,32] These state-of-the-art developments are in line with the hypothesis that the development of depression can involve an imbalance of the activity between different types of 5-HT isoreceptors [33,34]. It is known from our work that 5-HT1AR forms heteromers with many other receptors in membranes of the brain linked to the ascending 5-HT neurons [6,11,13,34,37,38,39,40,41,42,43,44]. 5-HT1AR agonist treatment [15,39]

Neurophysiological Studies

Behavioral Analysis

In Situ PLA Analysis

Multiple GalR–5-HT1A Heteroreceptor Complexes

Concluding

Methods