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

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.

Keywords: G protein-coupled receptors; depression; fibroblast growth factor receptor; galanin; heteroreceptor complexes; oligomerization; receptor tyrosine kinase; receptor-receptor interactions; serotonin 5-HT1A receptor.

Figure 1

Illustration of how serotonin volume transmission can reach the 5-HT1A–FGFR1, 5-HT1A–5-HT2A, GalR1–5-HT1A, and GalR1–GalR2–5-HT1A heteroreceptor complexes. The ligand for the GalR1–GalR2 heterodimer is the galanin fragment Gal (1–15), while galanin (1–19) is the ligand for galanin receptor monomers and homomers. The 5-HT1A heteroreceptor complexes may mainly have an extrasynaptic location, but also a synaptic location. They are proposed to modulate synaptic glutamate transmission in pyramidal neurons of the hippocampus and synaptic GABA transmission in inhibitory GABA interneurons of the hippocampus. The differential role of these hippocampal 5-HT1A heteroreceptor complexes in modulating the hippocampal networks remain to be characterized.

Figure 2

Illustration of the GalR1 and GalR2 homoreceptor complexes and the GalR1–GalR2 and 5-HT1A–GalR1–GalR2 heteroreceptor complexes in the plasma membrane. The major endogenous ligand for GalR1 and GalR2 homodimers is galanin 1–29, while the major ligand for the GalR1–GalR2 heterodimer is galanin 1–15. In the heterotrimer 5-HT1AR–GalR1–GalR2, the galanin fragment 1–15 may enhance the signaling of the 5-HT1A receptor protomer via a facilitatory allosteric receptor–receptor interaction involving mainly GalR2–5-HT1A receptor–receptor interactions.

Figure 3

Illustration of the distribution pattern of 5-HT1A–FGFR1 heteroreceptor and 5-HT1A–5-HT2A isoreceptor complexes visualized with PLA in the rat dorsal hippocampus. The 5-HT1A–FGFR1 heteroreceptor complexes, in red, have a more widespread distribution, mainly located within the pyramidal cell layer of the CA1–CA4 and in the plexiform cell layer of the dentate gyrus. However, they exist in low densities in the stratum oriens and radiatum of the CA1–CA4 regions and the subgranular layer. Instead, the 5-HT1A–5-HT2A isoreceptor complexes, shown in yellow, are concentrated to the pyramidal cell layer of the CA1–CA3 regions, with some located in the subgranular layer of the dentate gyrus.