Datensatz

Zusammenfassung

Serotonin receptors 5-HT_1A and 5-HT₇ are highly coexpressed in brain regions implicated in depression. However, their functional interaction has not been established. In the present study we show that 5-HT_1A and 5-HT₇ receptors form heterodimers both in vitro and in vivo. Foerster resonance energy transfer-based assays revealed that, in addition to heterodimers, homodimers composed either of 5-HT_1A or 5-HT₇ receptors together with monomers coexist in cells. The highest affinity for complex formation was obtained for the 5-HT₇–5-HT₇ homodimers, followed by the 5-HT₇–5-HT_1A heterodimers and 5-HT_1A–5-HT_1A homodimers. Functionally, heterodimerization decreases 5-HT_1A-receptor-mediated activation of Gi protein without affecting 5-HT7-receptor-mediated signalling. Moreover, heterodimerization markedly decreases the ability of the 5-HT_1A receptor to activate G-protein-gated inwardly rectifying potassium channels in a heterologous system. The inhibitory effect on such channels was also preserved in hippocampal neurons, demonstrating a physiological relevance of heteromerization in vivo. In addition, heterodimerization is crucially involved in initiation of the serotonin-mediated 5-HT_1A receptor internalization and also enhances the ability of the 5-HT_1A receptor to activate the mitogen-activated protein kinases. Finally, we found that production of 5-HT₇ receptors in the hippocampus continuously decreases during postnatal development, indicating that the relative concentration of 5-HT_1A–5-HT₇ heterodimers and, consequently, their functional importance undergoes pronounced developmental changes.